Journal articles: 'CaVβ1'

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Cohen, Risa M., Jason D. Foell, Ravi C. Balijepalli, Vaibhavi Shah, Johannes W. Hell, and Timothy J. Kamp. "Unique modulation of L-type Ca2+ channels by short auxiliary β1d subunit present in cardiac muscle." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 5 (May 2005): H2363—H2374. http://dx.doi.org/10.1152/ajpheart.00348.2004.

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Recent studies have identified a growing diversity of splice variants of auxiliary Ca2+ channel Cavβ subunits. The Cavβ1d isoform encodes a putative protein composed of the amino-terminal half of the full-length Cavβ1 isoform and thus lacks the known high-affinity binding site that recognizes the Ca2+ channel α1-subunit, the α-binding pocket. The present study investigated whether the Cavβ1d subunit is expressed at the protein level in heart, and whether it exhibits any of the functional properties typical of full-length Cavβ subunits. On Western blots, an antibody directed against the unique carboxyl terminus of Cavβ1d identified a protein of the predicted molecular mass of 23 kDa from canine and human hearts. Immunocytochemistry and surface-membrane biotinylation experiments in transfected HEK-293 cells revealed that the full-length Cavβ1b subunit promoted membrane trafficking of the pore-forming α1C (Cav1.2)-subunit to the surface membrane, whereas the Cavβ1d subunit did not. Whole cell patch-clamp analysis of transfected HEK-293 cells demonstrated no effect of coexpression of the Cavβ1d with the α1C-subunit compared with the 15-fold larger currents and leftward shift in voltage-dependent activation induced by full-length Cavβ1b coexpression. In contrast, cell-attached patch single-channel studies demonstrated that coexpression of either Cavβ1b or Cavβ1d significantly increased mean open probability four- to fivefold relative to the α1C-channels alone, but only Cavβ1b coexpression increased the number of channels observed per patch. In conclusion, the Cavβ1d isoform is expressed in heart and can modulate the gating of L-type Ca2+ channels, but it does not promote membrane trafficking of the channel complex.

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Foell, Jason D., Ravi C. Balijepalli, Brian P. Delisle, Anne Marie R. Yunker, Seth L. Robia, Jeffrey W. Walker, Maureen W. McEnery, Craig T. January, and Timothy J. Kamp. "Molecular heterogeneity of calcium channel β-subunits in canine and human heart: evidence for differential subcellular localization." Physiological Genomics 17, no. 2 (April 13, 2004): 183–200. http://dx.doi.org/10.1152/physiolgenomics.00207.2003.

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Multiple Ca2+ channel β-subunit (Cavβ) isoforms are known to differentially regulate the functional properties and membrane trafficking of high-voltage-activated Ca2+ channels, but the precise isoform expression pattern of Cavβ subunits in ventricular muscle has not been fully characterized. Using sequence data from the Human Genome Project to define the intron/exon structure of the four known Cavβ genes, we designed a systematic RT-PCR strategy to screen human and canine left ventricular myocardial samples for all known Cavβ isoforms. A total of 18 different Cavβ isoforms were detected in both canine and human ventricles including splice variants from all four Cavβ genes. Six of these isoforms have not previously been described. Western blots of ventricular membrane fractions and immunocytochemistry demonstrated that all four Cavβ subunit genes are expressed at the protein level, and the Cavβ subunits show differential subcellular localization with Cavβ1b, Cavβ2, and Cavβ3 predominantly localized to the T-tubule sarcolemma, whereas Cavβ1a and Cavβ4 are more prevalent in the surface sarcolemma. Coexpression of the novel Cavβ2c subunits (Cavβ2cN1, Cavβ2cN2, Cavβ2cN4) with the pore-forming α1C (Cav1.2) and Cavα2δ subunits in HEK 293 cells resulted in a marked increase in ionic current and Cavβ2c isoform-specific modulation of voltage-dependent activation. These results demonstrate a previously unappreciated heterogeneity of Cavβ subunit isoforms in ventricular myocytes and suggest the presence of different subcellular populations of Ca2+ channels with distinct functional properties.

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Despang, Patrick, Sarah Salamon, Alexandra Breitenkamp, Elza Kuzmenkina, and Jan Matthes. "Inhibitory effects on L- and N-type calcium channels by a novel CaVβ1 variant identified in a patient with autism spectrum disorder." Naunyn-Schmiedeberg's Archives of Pharmacology 395, no. 4 (February 5, 2022): 459–70. http://dx.doi.org/10.1007/s00210-022-02213-7.

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AbstractVoltage-gated calcium channel (VGCC) subunits have been genetically associated with autism spectrum disorders (ASD). The properties of the pore-forming VGCC subunit are modulated by auxiliary β-subunits, which exist in four isoforms (CaVβ1-4). Our previous findings suggested that activation of L-type VGCCs is a common feature of CaVβ2 subunit mutations found in ASD patients. In the current study, we functionally characterized a novel CaVβ1b variant (p.R296C) identified in an ASD patient. We used whole-cell and single-channel patch clamp to study the effect of CaVβ1b_R296C on the function of L- and N-type VGCCs. Furthermore, we used co-immunoprecipitation followed by Western blot to evaluate the interaction of the CaVβ1b-subunits with the RGK-protein Gem. Our data obtained at both, whole-cell and single-channel levels, show that compared to a wild-type CaVβ1b, the CaVβ1b_R296C variant inhibits L- and N-type VGCCs. Interaction with and modulation by the RGK-protein Gem seems to be intact. Our findings indicate functional effects of the CaVβ1b_R296C variant differing from that attributed to CaVβ2 variants found in ASD patients. Further studies have to detail the effects on different VGCC subtypes and on VGCC expression.

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Traoré, Massiré, Christel Gentil, Chiara Benedetto, Jean-Yves Hogrel, Pierre De la Grange, Bruno Cadot, Sofia Benkhelifa-Ziyyat, et al. "An embryonic CaVβ1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse." Science Translational Medicine 11, no. 517 (November 6, 2019): eaaw1131. http://dx.doi.org/10.1126/scitranslmed.aaw1131.

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Deciphering the mechanisms that govern skeletal muscle plasticity is essential to understand its pathophysiological processes, including age-related sarcopenia. The voltage-gated calcium channel CaV1.1 has a central role in excitation-contraction coupling (ECC), raising the possibility that it may also initiate the adaptive response to changes during muscle activity. Here, we revealed the existence of a gene transcription switch of the CaV1.1 β subunit (CaVβ1) that is dependent on the innervation state of the muscle in mice. In a mouse model of sciatic denervation, we showed increased expression of an embryonic isoform of the subunit that we called CaVβ1E. CaVβ1E boosts downstream growth differentiation factor 5 (GDF5) signaling to counteract muscle loss after denervation in mice. We further reported that aged mouse muscle expressed lower quantity of CaVβ1E compared with young muscle, displaying an altered GDF5-dependent response to denervation. Conversely, CaVβ1E overexpression improved mass wasting in aging muscle in mice by increasing GDF5 expression. We also identified the human CaVβ1E analogous and show a correlation between CaVβ1E expression in human muscles and age-related muscle mass decline. These results suggest that strategies targeting CaVβ1E or GDF5 might be effective in reducing muscle mass loss in aging.

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Belkacemi, Anouar, Andreas Beck, Barbara Wardas, Petra Weissgerber, and Veit Flockerzi. "IP3-dependent Ca2+ signals are tightly controlled by Cavβ3, but not by Cavβ1, 2 and 4." Cell Calcium 104 (June 2022): 102573. http://dx.doi.org/10.1016/j.ceca.2022.102573.

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Heneghan, John F., Tora Mitra-Ganguli, Lee F. Stanish, Liwang Liu, Rubing Zhao, and Ann R. Rittenhouse. "The Ca2+ channel β subunit determines whether stimulation of Gq-coupled receptors enhances or inhibits N current." Journal of General Physiology 134, no. 5 (October 26, 2009): 369–84. http://dx.doi.org/10.1085/jgp.200910203.

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In superior cervical ganglion (SCG) neurons, stimulation of M1 receptors (M1Rs) produces a distinct pattern of modulation of N-type calcium (N-) channel activity, enhancing currents elicited with negative test potentials and inhibiting currents elicited with positive test potentials. Exogenously applied arachidonic acid (AA) reproduces this profile of modulation, suggesting AA functions as a downstream messenger of M1Rs. In addition, techniques that diminish AA's concentration during M1R stimulation minimize N-current modulation. However, other studies suggest depletion of phosphatidylinositol-4,5-bisphosphate during M1R stimulation suffices to elicit modulation. In this study, we used an expression system to examine the physiological mechanisms regulating modulation. We found the β subunit (CaVβ) acts as a molecular switch regulating whether modulation results in enhancement or inhibition. In human embryonic kidney 293 cells, stimulation of M1Rs or neurokinin-1 receptors (NK-1Rs) inhibited activity of N channels formed by CaV2.2 and coexpressed with CaVβ1b, CaVβ3, or CaVβ4 but enhanced activity of N channels containing CaVβ2a. Exogenously applied AA produced the same pattern of modulation. Coexpression of CaVβ2a, CaVβ3, and CaVβ4 recapitulated the modulatory response previously seen in SCG neurons, implying heterogeneous association of CaVβ with CaV2.2. Further experiments with mutated, chimeric CaVβ subunits and free palmitic acid revealed that palmitoylation of CaVβ2a is essential for loss of inhibition. The data presented here fit a model in which CaVβ2a blocks inhibition, thus unmasking enhancement. Our discovery that the presence or absence of palmitoylated CaVβ2a toggles M1R- or NK-1R–mediated modulation of N current between enhancement and inhibition identifies a novel role for palmitoylation. Moreover, these findings predict that at synapses, modulation of N-channel activity by M1Rs or NK-1Rs will fluctuate between enhancement and inhibition based on the presence of palmitoylated CaVβ2a.

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Brown, Betty, M. Steven Oberste, Kaija Maher, and Mark A. Pallansch. "Complete Genomic Sequencing Shows that Polioviruses and Members of Human Enterovirus Species C Are Closely Related in the Noncapsid Coding Region." Journal of Virology 77, no. 16 (August 15, 2003): 8973–84. http://dx.doi.org/10.1128/jvi.77.16.8973-8984.2003.

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ABSTRACT The 65 human enterovirus serotypes are currently classified into five species: Poliovirus (3 serotypes), Human enterovirus A (HEV-A) (12 serotypes), HEV-B (37 serotypes), HEV-C (11 serotypes), and HEV-D (2 serotypes). Coxsackie A virus (CAV) serotypes 1, 11, 13, 15, 17, 18, 19, 20, 21, 22, and 24 constitute HEV-C. We have determined the complete genome sequences for the remaining nine HEV-C serotypes and compared them with the complete sequences of CAV21, CAV24, and the polioviruses. The viruses were most diverse in the capsid region (4 to 36% amino acid difference). A high degree of capsid sequence conservation (96% amino acid identity) suggests that CAV15 and CAV18 should be classified as strains of CAV11 and CAV13, respectively. In the 3CD region, CAV1, CAV19, and CAV22 differed from one another by only 1.2 to 1.4% and CAV11, CAV13, CAV17, CAV20, CAV21, CAV24, and the polioviruses differed from one another by only 1.2 to 3.6%. The two groups, however, differed from one another by 14.6 to 16.2%. The polioviruses as a group were monophyletic only in the capsid region. Only one group of serotypes (CAV1, CAV19, and CAV22) was consistently monophyletic in multiple genome regions. Incongruities among phylogenetic trees based on different genome regions strongly suggest that recombination has occurred between the polioviruses, CAV11, CAV13, CAV17, and CAV20. The close relationship among the polioviruses and CAV11, CAV13, CAV17, CAV20, CAV21, and CAV24 and the uniqueness of CAV1, CAV19, and CAV22 suggest that revisions should be made to the classification of these viruses.

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Taylor, Jackson, Tan Zhang, Laura Messi, Jiang Qian, Cristina Furdui, Claudia Hereñú, and Osvaldo Delbono. "The Cavβ1 Subunit Regulates Gene Expression in Muscle Progenitor Cells." Biophysical Journal 102, no. 3 (January 2012): 365a. http://dx.doi.org/10.1016/j.bpj.2011.11.1993.

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9

Traore, M., C. Gentil, C. Benedetto, J. Hogrel, P. De la Grange, S. Benkhelifa-Ziyyat, L. Julien, M. Lemaitre, A. Ferry, and S. Falcone. "P.133A novel CaVβ1 isoform connecting voltage sensing with muscle mass homeostasis." Neuromuscular Disorders 29 (October 2019): S87. http://dx.doi.org/10.1016/j.nmd.2019.06.189.

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Buraei, Zafir, and Jian Yang. "The β Subunit of Voltage-Gated Ca2+ Channels." Physiological Reviews 90, no. 4 (October 2010): 1461–506. http://dx.doi.org/10.1152/physrev.00057.2009.

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Calcium regulates a wide spectrum of physiological processes such as heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entryways for Ca2+ in excitable cells are high-voltage activated (HVA) Ca2+ channels. These are plasma membrane proteins composed of several subunits, including α1, α2δ, β, and γ. Although the principal α1 subunit (Cavα1) contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit (Cavβ) plays an essential role in regulating the surface expression and gating properties of HVA Ca2+ channels. Cavβ is also crucial for the modulation of HVA Ca2+ channels by G proteins, kinases, and the Ras-related RGK GTPases. New proteins have emerged in recent years that modulate HVA Ca2+ channels by binding to Cavβ. There are also indications that Cavβ may carry out Ca2+ channel-independent functions, including directly regulating gene transcription. All four subtypes of Cavβ, encoded by different genes, have a modular organization, consisting of three variable regions, a conserved guanylate kinase (GK) domain, and a conserved Src-homology 3 (SH3) domain, placing them into the membrane-associated guanylate kinase (MAGUK) protein family. Crystal structures of Cavβs reveal how they interact with Cavα1, open new research avenues, and prompt new inquiries. In this article, we review the structure and various biological functions of Cavβ, with both a historical perspective as well as an emphasis on recent advances.

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Park, Won Sun, Soon Chul Heo, Eun Su Jeon, Da Hye Hong, Youn Kyoung Son, Jae-Hong Ko, Hyoung Kyu Kim, Sun Young Lee, Jae Ho Kim, and Jin Han. "Functional expression of smooth muscle-specific ion channels in TGF-β1-treated human adipose-derived mesenchymal stem cells." American Journal of Physiology-Cell Physiology 305, no. 4 (August 15, 2013): C377—C391. http://dx.doi.org/10.1152/ajpcell.00404.2012.

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Human adipose tissue-derived mesenchymal stem cells (hASCs) have the power to differentiate into various cell types including chondrocytes, osteocytes, adipocytes, neurons, cardiomyocytes, and smooth muscle cells. We characterized the functional expression of ion channels after transforming growth factor-β1 (TGF-β1)-induced differentiation of hASCs, providing insights into the differentiation of vascular smooth muscle cells. The treatment of hASCs with TGF-β1 dramatically increased the contraction of a collagen-gel lattice and the expression levels of specific genes for smooth muscle including α-smooth muscle actin, calponin, smooth mucle-myosin heavy chain, smoothelin-B, myocardin, and h-caldesmon. We observed Ca2+, big-conductance Ca2+-activated K+ (BKCa), and voltage-dependent K+ (Kv) currents in TGF-β1-induced, differentiated hASCs and not in undifferentiated hASCs. The currents share the characteristics of vascular smooth muscle cells (SMCs). RT-PCR and Western blotting revealed that the L-type (Cav1.2) and T-type (Cav3.1, 3.2, and 3.3), known to be expressed in vascular SMCs, dramatically increased along with the Cavβ1 and Cavβ3 subtypes in TGF-β1-induced, differentiated hASCs. Although the expression-level changes of the β-subtype BKCa channels varied, the major α-subtype BKCa channel (KCa1.1) clearly increased in the TGF-β1-induced, differentiated hASCs. Most of the Kv subtypes, also known to be expressed in vascular SMCs, dramatically increased in the TGF-β1-induced, differentiated hASCs. Our results suggest that TGF-β1 induces the increased expression of vascular SMC-like ion channels and the differentiation of hASCs into contractile vascular SMCs.

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Xie, Mian, Xiang Li, Jing Han, Daniel L. Vogt, Silke Wittemann, Melanie D. Mark, and Stefan Herlitze. "Facilitation versus depression in cultured hippocampal neurons determined by targeting of Ca2+ channel Cavβ4 versus Cavβ2 subunits to synaptic terminals." Journal of Cell Biology 178, no. 3 (July 30, 2007): 489–502. http://dx.doi.org/10.1083/jcb.200702072.

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Ca2+ channel β subunits determine the transport and physiological properties of high voltage–activated Ca2+ channel complexes. Our analysis of the distribution of the Cavβ subunit family members in hippocampal neurons correlates their synaptic distribution with their involvement in transmitter release. We find that exogenously expressed Cavβ4b and Cavβ2a subunits distribute in clusters and localize to synapses, whereas Cavβ1b and Cavβ3 are homogenously distributed. According to their localization, Cavβ2a and Cavβ4b subunits modulate the synaptic plasticity of autaptic hippocampal neurons (i.e., Cavβ2a induces depression, whereas Cavβ4b induces paired-pulse facilitation [PPF] followed by synaptic depression during longer stimuli trains). The induction of PPF by Cavβ4b correlates with a reduction in the release probability and cooperativity of the transmitter release. These results suggest that Cavβ subunits determine the gating properties of the presynaptic Ca2+ channels within the presynaptic terminal in a subunit-specific manner and may be involved in organization of the Ca2+ channel relative to the release machinery.

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Béguin, Pascal, Kazuaki Nagashima, Ramasubbu N. Mahalakshmi, Réjan Vigot, Atsuko Matsunaga, Takafumi Miki, Mei Yong Ng, et al. "BARP suppresses voltage-gated calcium channel activity and Ca2+-evoked exocytosis." Journal of Cell Biology 205, no. 2 (April 21, 2014): 233–49. http://dx.doi.org/10.1083/jcb.201304101.

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Voltage-gated calcium channels (VGCCs) are key regulators of cell signaling and Ca2+-dependent release of neurotransmitters and hormones. Understanding the mechanisms that inactivate VGCCs to prevent intracellular Ca2+ overload and govern their specific subcellular localization is of critical importance. We report the identification and functional characterization of VGCC β-anchoring and -regulatory protein (BARP), a previously uncharacterized integral membrane glycoprotein expressed in neuroendocrine cells and neurons. BARP interacts via two cytosolic domains (I and II) with all Cavβ subunit isoforms, affecting their subcellular localization and suppressing VGCC activity. Domain I interacts at the α1 interaction domain–binding pocket in Cavβ and interferes with the association between Cavβ and Cavα1. In the absence of domain I binding, BARP can form a ternary complex with Cavα1 and Cavβ via domain II. BARP does not affect cell surface expression of Cavα1 but inhibits Ca2+ channel activity at the plasma membrane, resulting in the inhibition of Ca2+-evoked exocytosis. Thus, BARP can modulate the localization of Cavβ and its association with the Cavα1 subunit to negatively regulate VGCC activity.

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Findeisen, Felix, and Daniel L. Minor. "Disruption of the IS6-AID Linker Affects Voltage-gated Calcium Channel Inactivation and Facilitation." Journal of General Physiology 133, no. 3 (February 23, 2009): 327–43. http://dx.doi.org/10.1085/jgp.200810143.

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Two processes dominate voltage-gated calcium channel (CaV) inactivation: voltage-dependent inactivation (VDI) and calcium-dependent inactivation (CDI). The CaVβ/CaVα1-I-II loop and Ca2+/calmodulin (CaM)/CaVα1–C-terminal tail complexes have been shown to modulate each, respectively. Nevertheless, how each complex couples to the pore and whether each affects inactivation independently have remained unresolved. Here, we demonstrate that the IS6–α-interaction domain (AID) linker provides a rigid connection between the pore and CaVβ/I-II loop complex by showing that IS6-AID linker polyglycine mutations accelerate CaV1.2 (L-type) and CaV2.1 (P/Q-type) VDI. Remarkably, mutations that either break the rigid IS6-AID linker connection or disrupt CaVβ/I-II association sharply decelerate CDI and reduce a second Ca2+/CaM/CaVα1–C-terminal–mediated process known as calcium-dependent facilitation. Collectively, the data strongly suggest that components traditionally associated solely with VDI, CaVβ and the IS6-AID linker, are essential for calcium-dependent modulation, and that both CaVβ-dependent and CaM-dependent components couple to the pore by a common mechanism requiring CaVβ and an intact IS6-AID linker.

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Gonzalez-Gutierrez, Giovanni, Erick Miranda-Laferte, David Naranjo, Patricia Hidalgo, and Alan Neely. "Mutations of Nonconserved Residues within the Calcium Channel α1-interaction Domain Inhibit β-Subunit Potentiation." Journal of General Physiology 132, no. 3 (August 25, 2008): 383–95. http://dx.doi.org/10.1085/jgp.200709901.

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Voltage-dependent calcium channels consist of a pore-forming subunit (CaVα1) that includes all the molecular determinants of a voltage-gated channel, and several accessory subunits. The ancillary β-subunit (CaVβ) is a potent activator of voltage-dependent calcium channels, but the mechanisms and structural bases of this regulation remain elusive. CaVβ binds reversibly to a conserved consensus sequence in CaVα1, the α1-interaction domain (AID), which forms an α-helix when complexed with CaVβ. Conserved aromatic residues face to one side of the helix and strongly interact with a hydrophobic pocket on CaVβ. Here, we studied the effect of mutating residues located opposite to the AID-CaVβ contact surface in CaV1.2. Substitution of AID-exposed residues by the corresponding amino acids present in other CaVα1 subunits (E462R, K465N, D469S, and Q473K) hinders CaVβ's ability to increase ionic-current to charge-movement ratio (I/Q) without changing the apparent affinity for CaVβ. At the single channel level, these CaV1.2 mutants coexpressed with CaVβ2a visit high open probability mode less frequently than wild-type channels. On the other hand, CaV1.2 carrying either a mutation in the conserved tryptophan residue (W470S, which impairs CaVβ binding), or a deletion of the whole AID sequence, does not exhibit CaVβ-induced increase in I/Q. In addition, we observed a shift in the voltage dependence of activation by +12 mV in the AID-deleted channel in the absence of CaVβ, suggesting a direct participation of these residues in the modulation of channel activation. Our results show that CaVβ-dependent potentiation arises primarily from changes in the modal gating behavior. We envision that CaVβ spatially reorients AID residues that influence the channel gate. These findings provide a new framework for understanding modulation of VDCC gating by CaVβ.

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Romano, Antonella, Antonia Feola, Antonio Porcellini, Vincenzo Gigantino, Maurizio Di Bonito, Annabella Di Mauro, Rocco Caggiano, Raffaella Faraonio, and Candida Zuchegna. "Estrogen Induces Selective Transcription of Caveolin1 Variants in Human Breast Cancer through Estrogen Responsive Element-Dependent Mechanisms." International Journal of Molecular Sciences 21, no. 17 (August 20, 2020): 5989. http://dx.doi.org/10.3390/ijms21175989.

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The estrogen receptor (ER) signaling regulates numerous physiological processes mainly through activation of gene transcription (genomic pathways). Caveolin1 (CAV1) is a membrane-resident protein that behaves as platform to enable different signaling molecules and receptors for membrane-initiated pathways. CAV1 directly interacts with ERs and allows their localization on membrane with consequent activation of ER-non-genomic pathways. Loss of CAV1 function is a common feature of different types of cancers, including breast cancer. Two protein isoforms, CAV1α and CAV1β, derived from two alternative translation initiation sites, are commonly described for this gene. However, the exact transcriptional regulation underlying CAV1 expression pattern is poorly elucidated. In this study, we dissect the molecular mechanism involved in selective expression of CAV1β isoform, induced by estrogens and downregulated in breast cancer. Luciferase assays and Chromatin immunoprecipitation demonstrate that transcriptional activation is triggered by estrogen-responsive elements embedded in CAV1 intragenic regions and DNA-binding of estrogen-ER complexes. This regulatory control is dynamically established by local chromatin changes, as proved by the occurrence of histone H3 methylation/demethylation events and association of modifier proteins as well as modification of H3 acetylation status. Thus, we demonstrate for the first time, an estrogen-ERs-dependent regulatory circuit sustaining selective CAV1β expression.

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Jha, Mithilesh, Archana Jha, Ashish Singh, Petra Weissgerber, Marc Freichel, Veit Flockerzi, and Richard Flavell. "Essential role of Cavβ2 in T Cell development and homeostasis. (LYM7P.715)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 193.3. http://dx.doi.org/10.4049/jimmunol.192.supp.193.3.

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Abstract Although many of the molecular components that regulate TCR signaling and thymocyte development are well characterized, the interactions between these molecules and their assembly in signaling complexes have remained elusive. Here, we report a novel and intriguing role of β2 regulatory subunit of voltage gated calcium channels (Cavβ2) during T cells development in thymus. We found that the T cell specific ablation of Cavβ2 resulted in severe reduction in thymocytes. Cavβ2-deficient DN and DP thymocytes were prone to die spontaneously. Consequently, the lack of Cavβ2 led to substantially lower peripheral T cell numbers, which became even more prominent in a competitive environment, thus emphasizing the crucial function of Cavβ2 in maintaining the peripheral T cell pool. Nicardipine, a selective Cav1 channel blocker, abolished the constitutive Lck phosphorylation in thymocytes and impacted the sustained calcium influx upon TCR-stimulation. The in vivo treatment of nicardipine resulted in a dramatic reduction in number of thymocytes and T cells but not bone marrow cells. Our findings demonstrate that Cavβ2 and Cav1 channels are critical components required during development and homeostasis of T cells.

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Taylor, Jackson, Andrea Pereyra, Tan Zhang, Maria Laura Messi, Zhong-Min Wang, Claudia Hereñú, Pei-Fen Kuan, and Osvaldo Delbono. "The Cavβ1a subunit regulates gene expression and suppresses myogenin in muscle progenitor cells." Journal of Cell Biology 205, no. 6 (June 16, 2014): 829–46. http://dx.doi.org/10.1083/jcb.201403021.

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Voltage-gated calcium channel (Cav) β subunits are auxiliary subunits to Cavs. Recent reports show Cavβ subunits may enter the nucleus and suggest a role in transcriptional regulation, but the physiological relevance of this localization remains unclear. We sought to define the nuclear function of Cavβ in muscle progenitor cells (MPCs). We found that Cavβ1a is expressed in proliferating MPCs, before expression of the calcium conducting subunit Cav1.1, and enters the nucleus. Loss of Cavβ1a expression impaired MPC expansion in vitro and in vivo and caused widespread changes in global gene expression, including up-regulation of myogenin. Additionally, we found that Cavβ1a localizes to the promoter region of a number of genes, preferentially at noncanonical (NC) E-box sites. Cavβ1a binds to a region of the Myog promoter containing an NC E-box, suggesting a mechanism for inhibition of myogenin gene expression. This work indicates that Cavβ1a acts as a Cav-independent regulator of gene expression in MPCs, and is required for their normal expansion during myogenic development.

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An, Mingwei, Xueling Chen, Zhuhong Yang, Jianyu Zhou, Shan Ye, and Zhong Ding. "Co-Silencing of the Voltage-Gated Calcium Channel β Subunit and High-Voltage Activated α1 Subunit by dsRNA Soaking Resulted in Enhanced Defects in Locomotion, Stylet Thrusting, Chemotaxis, Protein Secretion, and Reproduction in Ditylenchus destructor." International Journal of Molecular Sciences 23, no. 2 (January 11, 2022): 784. http://dx.doi.org/10.3390/ijms23020784.

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The voltage-gated calcium channel (VGCC) β subunit (Cavβ) protein is a kind of cytosolic auxiliary subunit that plays an important role in regulating the surface expression and gating characteristics of high-voltage-activated (HVA) calcium channels. Ditylenchus destructor is an important plant-parasitic nematode. In the present study, the putative Cavβ subunit gene of D. destructor, namely, DdCavβ, was subjected to molecular characterization. In situ hybridization assays showed that DdCavβ was expressed in all nematode tissues. Transcriptional analyses showed that DdCavβ was expressed during each developmental stage of D. destructor, and the highest expression level was recorded in the third-stage juveniles. The crucial role of DdCavβ was verified by dsRNA soaking-mediated RNA interference (RNAi). Silencing of DdCavβ or HVA Cavα1 alone and co-silencing of the DdCavβ and HVA Cavα1 genes resulted in defective locomotion, stylet thrusting, chemotaxis, protein secretion and reproduction in D. destructor. Co-silencing of the HVA Cavα1 and Cavβ subunits showed stronger interference effects than single-gene silencing. This study provides insights for further study of VGCCs in plant-parasitic nematodes.

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Catalucci, Daniele, Deng-Hong Zhang, Jaime DeSantiago, Franck Aimond, Guillaume Barbara, Jean Chemin, Désiré Bonci, et al. "Akt regulates L-type Ca2+ channel activity by modulating Cavα1 protein stability." Journal of Cell Biology 184, no. 6 (March 23, 2009): 923–33. http://dx.doi.org/10.1083/jcb.200805063.

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The insulin IGF-1–PI3K–Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca2+ handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca2+ channel (LTCC) protein density. The pore-forming channel subunit Cavα1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Cavα1 protein levels. Our findings show that Akt-dependent phosphorylation of Cavβ2, the LTCC chaperone for Cavα1, antagonizes Cavα1 protein degradation by preventing Cavα1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca2+ channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myocyte Ca2+ entry, Ca2+ handling, and contractility.

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Puckerin, Akil A., Donald D. Chang, Zunaira Shuja, Papiya Choudhury, Joachim Scholz, and Henry M. Colecraft. "Engineering selectivity into RGK GTPase inhibition of voltage-dependent calcium channels." Proceedings of the National Academy of Sciences 115, no. 47 (November 5, 2018): 12051–56. http://dx.doi.org/10.1073/pnas.1811024115.

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Genetically encoded inhibitors for voltage-dependent Ca2+ (CaV) channels (GECCIs) are useful research tools and potential therapeutics. Rad/Rem/Rem2/Gem (RGK) proteins are Ras-like G proteins that potently inhibit high voltage-activated (HVA) Ca2+ (CaV1/CaV2 family) channels, but their nonselectivity limits their potential applications. We hypothesized that nonselectivity of RGK inhibition derives from their binding to auxiliary CaVβ-subunits. To investigate latent CaVβ-independent components of inhibition, we coexpressed each RGK individually with CaV1 (CaV1.2/CaV1.3) or CaV2 (CaV2.1/CaV2.2) channels reconstituted in HEK293 cells with either wild-type (WT) β2a or a mutant version (β2a,TM) that does not bind RGKs. All four RGKs strongly inhibited CaV1/CaV2 channels reconstituted with WT β2a. By contrast, when channels were reconstituted with β2a,TM, Rem inhibited only CaV1.2, Rad selectively inhibited CaV1.2 and CaV2.2, while Gem and Rem2 were ineffective. We generated mutant RGKs (Rem[R200A/L227A] and Rad[R208A/L235A]) unable to bind WT CaVβ, as confirmed by fluorescence resonance energy transfer. Rem[R200A/L227A] selectively blocked reconstituted CaV1.2 while Rad[R208A/L235A] inhibited CaV1.2/CaV2.2 but not CaV1.3/CaV2.1. Rem[R200A/L227A] and Rad[R208A/L235A] both suppressed endogenous CaV1.2 channels in ventricular cardiomyocytes and selectively blocked 25 and 62%, respectively, of HVA currents in somatosensory neurons of the dorsal root ganglion, corresponding to their distinctive selectivity for CaV1.2 and CaV1.2/CaV2.2 channels. Thus, we have exploited latent β-binding–independent Rem and Rad inhibition of specific CaV1/CaV2 channels to develop selective GECCIs with properties unmatched by current small-molecule CaV channel blockers.

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Mitra-Ganguli, Tora, Iuliia Vitko, Edward Perez-Reyes, and Ann R. Rittenhouse. "Orientation of palmitoylated CaVβ2a relative to CaV2.2 is critical for slow pathway modulation of N-type Ca2+ current by tachykinin receptor activation." Journal of General Physiology 134, no. 5 (October 26, 2009): 385–96. http://dx.doi.org/10.1085/jgp.200910204.

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The Gq-coupled tachykinin receptor (neurokinin-1 receptor [NK-1R]) modulates N-type Ca2+ channel (CaV2.2 or N channel) activity at two distinct sites by a pathway involving a lipid metabolite, most likely arachidonic acid (AA). In another study published in this issue (Heneghan et al. 2009. J. Gen Physiol. doi:10.1085/jgp.200910203), we found that the form of modulation observed depends on which CaVβ is coexpressed with CaV2.2. When palmitoylated CaVβ2a is coexpressed, activation of NK-1Rs by substance P (SP) enhances N current. In contrast, when CaVβ3 is coexpressed, SP inhibits N current. However, exogenously applied palmitic acid minimizes this inhibition. These findings suggested that the palmitoyl groups of CaVβ2a may occupy an inhibitory site on CaV2.2 or prevent AA from interacting with that site, thereby minimizing inhibition. If so, changing the orientation of CaVβ2a relative to CaV2.2 may displace the palmitoyl groups and prevent them from antagonizing AA's actions, thereby allowing inhibition even in the presence of CaVβ2a. In this study, we tested this hypothesis by deleting one (Bdel1) or two (Bdel2) amino acids proximal to the α interacting domain (AID) of CaV2.2's I–II linker. CaVβs bind tightly to the AID, whereas the rigid region proximal to the AID is thought to couple CaVβ's movements to CaV2.2 gating. Although Bdel1/β2a currents exhibited more variable enhancement by SP, Bdel2/β2a current enhancement was lost at all voltages. Instead, inhibition was observed that matched the profile of N-current inhibition from CaV2.2 coexpressed with CaVβ3. Moreover, adding back exogenous palmitic acid minimized inhibition of Bdel2/β2a currents, suggesting that when palmitoylated CaVβ2a is sufficiently displaced, endogenously released AA can bind to the inhibitory site. These findings support our previous hypothesis that CaVβ2a's palmitoyl groups directly interact with an inhibitory site on CaV2.2 to block N-current inhibition by SP.

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Meissner, Marcel, Petra Weissgerber, Juan E. Camacho Londoño, Jean Prenen, Sabine Link, Sandra Ruppenthal, Jeffery D. Molkentin, et al. "Moderate Calcium Channel Dysfunction in Adult Mice with Inducible Cardiomyocyte-specific Excision of the cacnb2 Gene." Journal of Biological Chemistry 286, no. 18 (February 28, 2011): 15875–82. http://dx.doi.org/10.1074/jbc.m111.227819.

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The major L-type voltage-gated calcium channels in heart consist of an α1C (CaV1.2) subunit usually associated with an auxiliary β subunit (CaVβ2). In embryonic cardiomyocytes, both the complete and the cardiac myocyte-specific null mutant of CaVβ2 resulted in reduction of L-type calcium currents by up to 75%, compromising heart function and causing defective remodeling of intra- and extra-embryonic blood vessels followed by embryonic death. Here we conditionally excised the CaVβ2 gene (cacnb2) specifically in cardiac myocytes of adult mice (KO). Upon gene deletion, CaVβ2 protein expression declined by >96% in isolated cardiac myocytes and by >74% in protein fractions from heart. These latter protein fractions include CaVβ2 proteins expressed in cardiac fibroblasts. Surprisingly, mice did not show any obvious impairment, although cacnb2 excision was not compensated by expression of other CaVβ proteins or changes of CaV1.2 protein levels. Calcium currents were still dihydropyridine-sensitive, but current density at 0 mV was reduced by <29%. The voltage for half-maximal activation was slightly shifted to more depolarized potentials in KO cardiomyocytes when compared with control cells, but the difference was not significant. In summary, CaVβ2 appears to be a much stronger modulator of L-type calcium currents in embryonic than in adult cardiomyocytes. Although essential for embryonic survival, CaVβ2 down-regulation in cardiomyocytes is well tolerated by the adult mice.

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Chen, Xingjuan, Degang Liu, Donghui Zhou, Yubing Si, David Xu, Christopher W. Stamatkin, Mona K. Ghozayel, et al. "Small-molecule CaVα1⋅CaVβ antagonist suppresses neuronal voltage-gated calcium-channel trafficking." Proceedings of the National Academy of Sciences 115, no. 45 (October 24, 2018): E10566—E10575. http://dx.doi.org/10.1073/pnas.1813157115.

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Extracellular calcium flow through neuronal voltage-gated CaV2.2 calcium channels converts action potential-encoded information to the release of pronociceptive neurotransmitters in the dorsal horn of the spinal cord, culminating in excitation of the postsynaptic central nociceptive neurons. The CaV2.2 channel is composed of a pore-forming α1subunit (CaVα1) that is engaged in protein–protein interactions with auxiliary α2/δ and β subunits. The high-affinity CaV2.2α1⋅CaVβ3protein–protein interaction is essential for proper trafficking of CaV2.2 channels to the plasma membrane. Here, structure-based computational screening led to small molecules that disrupt the CaV2.2α1⋅CaVβ3protein–protein interaction. The binding mode of these compounds reveals that three substituents closely mimic the side chains of hot-spot residues located on the α-helix of CaV2.2α1. Site-directed mutagenesis confirmed the critical nature of a salt-bridge interaction between the compounds and CaVβ3Arg-307. In cells, compounds decreased trafficking of CaV2.2 channels to the plasma membrane and modulated the functions of the channel. In a rodent neuropathic pain model, the compounds suppressed pain responses. Small-molecule α-helical mimetics targeting ion channel protein–protein interactions may represent a strategy for developing nonopioid analgesia and for treatment of other neurological disorders associated with calcium-channel trafficking.

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Al Katat, Aya, Juan Zhao, Angelino Calderone, and Lucie Parent. "Sympathetic Stimulation Upregulates the Ca2+ Channel Subunit, CaVα2δ1, via the β1 and ERK 1/2 Pathway in Neonatal Ventricular Cardiomyocytes." Cells 11, no. 2 (January 6, 2022): 188. http://dx.doi.org/10.3390/cells11020188.

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Intracellular Ca2+ overload secondary to chronic hemodynamic stimuli promotes the recruitment of Ca2+-dependent signaling implicated in cardiomyocyte hypertrophy. The present study tested the hypothesis that sympathetic-mediated hypertrophy of neonatal rat ventricular cardiomyocytes (NRVMs) translated to an increase in calcium influx secondary to the upregulation of CaV1.2 channel subunits. Confocal imaging of norepinephrine (NE)-treated NRVMs revealed a hypertrophic response compared to untreated NRVMs. L-type CaV1.2 peak current density was increased 4-fold following a 24-h stimulation with NE. NE-treated NRVMs exhibited a significant upregulation of CaVα2δ1 and CaVβ3 protein levels without significant changes of CaVα1C and CaVβ2 protein levels. Pre-treatment with the β1-blocker metoprolol failed to inhibit hypertrophy or CaVβ3 upregulation whereas CaVα2δ1 protein levels were significantly reduced. NE promoted the phosphorylation of ERK 1/2, and the response was attenuated by the β1-blocker. U0126 pre-treatment suppressed NE-induced ERK1/2 phosphorylation but failed to attenuate hypertrophy. U0126 inhibition of ERK1/2 phosphorylation prevented NE-mediated upregulation of CaVα2δ1, whereas CaVβ3 protein levels remained elevated. Thus, β1-adrenergic receptor-mediated recruitment of the ERK1/2 plays a seminal role in the upregulation of CaVα2δ1 in NRVMs independent of the concomitant hypertrophic response. However, the upregulation of CaVβ3 protein levels may be directly dependent on the hypertrophic response of NRVMs.

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Jangsangthong, Wanchana, Elza Kuzmenkina, Ann Kristin Böhnke, and Stefan Herzig. "Single-Channel Monitoring of Reversible L-Type Ca2+ Channel CaVα1-CaVβ Subunit Interaction." Biophysical Journal 101, no. 11 (December 2011): 2661–70. http://dx.doi.org/10.1016/j.bpj.2011.09.063.

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Jha, Archana, Ashish K. Singh, Petra Weissgerber, Marc Freichel, Veit Flockerzi, Richard A. Flavell, and Mithilesh K. Jha. "Essential roles for Cavβ2 and Cav1 channels in thymocyte development and T cell homeostasis." Science Signaling 8, no. 399 (October 20, 2015): ra103. http://dx.doi.org/10.1126/scisignal.aac7538.

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Roberts-Crowley, Mandy L., and Ann R. Rittenhouse. "Arachidonic acid inhibition of L-type calcium (CaV1.3b) channels varies with accessory CaVβ subunits." Journal of General Physiology 133, no. 4 (March 30, 2009): 387–403. http://dx.doi.org/10.1085/jgp.200810047.

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Arachidonic acid (AA) inhibits the activity of several different voltage-gated Ca2+ channels by an unknown mechanism at an unknown site. The Ca2+ channel pore-forming subunit (CaVα1) is a candidate for the site of AA inhibition because T-type Ca2+ channels, which do not require accessory subunits for expression, are inhibited by AA. Here, we report the unanticipated role of accessory CaVβ subunits on the inhibition of CaV1.3b L-type (L-) current by AA. Whole cell Ba2+ currents were measured from recombinant channels expressed in human embryonic kidney 293 cells at a test potential of −10 mV from a holding potential of −90 mV. A one-minute exposure to 10 µM AA inhibited currents with β1b, β3, or β4 58, 51, or 44%, respectively, but with β2a only 31%. At a more depolarized holding potential of −60 mV, currents were inhibited to a lesser degree. These data are best explained by a simple model where AA stabilizes CaV1.3b in a deep closed-channel conformation, resulting in current inhibition. Consistent with this hypothesis, inhibition by AA occurred in the absence of test pulses, indicating that channels do not need to open to become inhibited. AA had no effect on the voltage dependence of holding potential–dependent inactivation or on recovery from inactivation regardless of CaVβ subunit. Unexpectedly, kinetic analysis revealed evidence for two populations of L-channels that exhibit willing and reluctant gating previously described for CaV2 channels. AA preferentially inhibited reluctant gating channels, revealing the accelerated kinetics of willing channels. Additionally, we discovered that the palmitoyl groups of β2a interfere with inhibition by AA. Our novel findings that the CaVβ subunit alters kinetic changes and magnitude of inhibition by AA suggest that CaVβ expression may regulate how AA modulates Ca2+-dependent processes that rely on L-channels, such as gene expression, enzyme activation, secretion, and membrane excitability.

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Bennett, Robert. "Reflecting on Editorial and Publishing Challenges: Government and Policy; The First 25 Years." Environment and Planning C: Government and Policy 26, no. 1 (January 2008): 1–16. http://dx.doi.org/10.1068/cav1.

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Park, Heonyong, Young-Mi Go, Ritesh Darji, Jong-Whan Choi, Michael P. Lisanti, Matthew C. Maland, and Hanjoong Jo. "Caveolin-1 regulates shear stress-dependent activation of extracellular signal-regulated kinase." American Journal of Physiology-Heart and Circulatory Physiology 278, no. 4 (April 1, 2000): H1285—H1293. http://dx.doi.org/10.1152/ajpheart.2000.278.4.h1285.

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Fluid shear stress activates a member of the mitogen-activated protein (MAP) kinase family, extracellular signal-regulated kinase (ERK), by mechanisms dependent on cholesterol in the plasma membrane in bovine aortic endothelial cells (BAEC). Caveolae are microdomains of the plasma membrane that are enriched with cholesterol, caveolin, and signaling molecules. We hypothesized that caveolin-1 regulates shear activation of ERK. Because caveolin-1 is not exposed to the outside, cells were minimally permeabilized by Triton X-100 (0.01%) to deliver a neutralizing, polyclonal caveolin-1 antibody (pCav-1) inside the cells. pCav-1 then bound to caveolin-1 and inhibited shear activation of ERK but not c-Jun NH2-terminal kinase. Epitope mapping studies showed that pCav-1 binds to caveolin-1 at two regions (residues 1–21 and 61–101). When the recombinant proteins containing the epitopes fused to glutathione- S-transferase (GST-Cav1–21 or GST-Cav61–101) were preincubated with pCav-1, only GST-Cav61–101 reversed the inhibitory effect of the antibody on shear activation of ERK. Other antibodies, including m2234, which binds to caveolin-1 residues 1–21, had no effect on shear activation of ERK. Caveolin-1 residues 61–101 contain the scaffolding and oligomerization domains, suggesting that binding of pCav-1 to these regions likely disrupts the clustering of caveolin-1 or its interaction with signaling molecules involved in the shear-sensitive ERK pathway. We suggest that caveolae-like domains play a critical role in the mechanosensing and/or mechanosignal transduction of the ERK pathway.

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Van Petegem, Filip, Karl E. Duderstadt, Kimberly A. Clark, Michelle Wang, and Daniel L. Minor. "Alanine-Scanning Mutagenesis Defines a Conserved Energetic Hotspot in the CaVα1 AID-CaVβ Interaction Site that Is Critical for Channel Modulation." Structure 16, no. 2 (February 2008): 280–94. http://dx.doi.org/10.1016/j.str.2007.11.010.

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Colvin, Robert B. "CADI, Canti, Cavi1." Transplantation 83, no. 6 (March 2007): 677–78. http://dx.doi.org/10.1097/01.tp.0000262011.05196.a1.

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Croager, Emma. "CAV1 connection." Nature Reviews Cancer 4, no. 2 (February 2004): 90–91. http://dx.doi.org/10.1038/nrc1283.

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Bernardo, José F., Clara E. Magyar, W. Bruce Sneddon, and Peter A. Friedman. "Impaired renal calcium absorption in mice lacking calcium channel β3 subunits." Canadian Journal of Physiology and Pharmacology 87, no. 7 (July 2009): 522–30. http://dx.doi.org/10.1139/y09-035.

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Transgenic mice lacking calcium channel β3 subunits (CaVβ3) were used to determine the involvement of a multimeric calcium channel in mediating stimulated renal calcium absorption. We measured the ability of calcium channel β3 subunit-null (CaVβ3−/−) and wild-type (CaVβ3+/+) mice to increase renal calcium absorption in response to the calcium-sparing diuretic chlorothiazide (CTZ). Control rates of fractional sodium excretion were comparable in CaVβ3−/− and CaVβ3+/+ mice and CTZ increased sodium excretion similarly in both groups. CTZ enhanced calcium absorption only in wild-type CaVβ3+/+ mice. This effect was specific for diuretics acting on distal tubules because both CaVβ3−/− and CaVβ3+/+ mice responded comparably to furosemide. The absence of β3 subunits resulted in compensatory increases of TrpV5 calcium channels, the plasma membrane Ca-ATPase, NCX1 Na/Ca exchanger protein, and calbindin-D9k but not calbindin-D28k. We conclude that TrpV5 mediates basal renal calcium absorption and that a multimeric calcium channel that includes CaVβ3 mediates stimulated calcium transport.

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Copeland, Courtney A., Bing Han, Ajit Tiwari, Eric D. Austin, James E. Loyd, James D. West, and Anne K. Kenworthy. "A disease-associated frameshift mutation in caveolin-1 disrupts caveolae formation and function through introduction of a de novo ER retention signal." Molecular Biology of the Cell 28, no. 22 (November 2017): 3095–111. http://dx.doi.org/10.1091/mbc.e17-06-0421.

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Caveolin-1 (CAV1) is an essential component of caveolae and is implicated in numerous physiological processes. Recent studies have identified heterozygous mutations in the CAV1 gene in patients with pulmonary arterial hypertension (PAH), but the mechanisms by which these mutations impact caveolae assembly and contribute to disease remain unclear. To address this question, we examined the consequences of a familial PAH-associated frameshift mutation in CAV1, P158PfsX22, on caveolae assembly and function. We show that C-terminus of the CAV1 P158 protein contains a functional ER-retention signal that inhibits ER exit and caveolae formation and accelerates CAV1 turnover in Cav1–/– MEFs. Moreover, when coexpressed with wild-type (WT) CAV1 in Cav1–/– MEFs, CAV1-P158 functions as a dominant negative by partially disrupting WT CAV1 trafficking. In patient skin fibroblasts, CAV1 and caveolar accessory protein levels are reduced, fewer caveolae are observed, and CAV1 complexes exhibit biochemical abnormalities. Patient fibroblasts also exhibit decreased resistance to a hypo-osmotic challenge, suggesting the function of caveolae as membrane reservoir is compromised. We conclude that the P158PfsX22 frameshift introduces a gain of function that gives rise to a dominant negative form of CAV1, defining a new mechanism by which disease-associated mutations in CAV1 impair caveolae assembly.

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El-Yazbi, Ahmed F., Woo Jung Cho, Richard Schulz, and Edwin E. Daniel. "Caveolin-1 knockout alters β-adrenoceptors function in mouse small intestine." American Journal of Physiology-Gastrointestinal and Liver Physiology 291, no. 6 (December 2006): G1020—G1030. http://dx.doi.org/10.1152/ajpgi.00159.2006.

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β-Adrenoceptors are G protein-coupled receptors whose functions are closely associated with caveolae in the heart and cultured cell lines. In the gut, they are responsible, at least in part, for the mediation of the sympathetic stimulation that might lead to intestinal paralysis postoperatively. We examined the effect of caveolin-1 knockout on the β-adrenoceptor response in mouse small intestine. The relaxation response to (−)-isoprenaline in carbachol-contracted small intestinal tissue segments was reduced in caveolin-1 knockout mice (cav1−/−) compared with their genetic controls (cav1+/+). Immunohistochemical staining showed that β-adrenoceptor expression was similar in both strains in gut smooth muscle. Selective β-adrenoceptor blockers shifted the concentration response curve (CRC) of (−)-isoprenaline to the right in cav1+/+ intestine, but not in cav1−/−, with greatest shift in case of the β3-blocker, SR59230A. The CRC of the selective β3-agonist BRL 37344 was also shifted to the right in cav1−/− compared with cav1+/+. The cAMP-dependent protein kinase (PKA) inhibitor H-89 shifted the CRC of (−)-isoprenaline to the right in cav1+/+ but not in cav1−/−. H-89 reduced the relaxation due to forskolin and dibutyryl cAMP in cav1+/+ but not in cav1−/−, suggesting a reduction in PKA activity in cav1−/−. In cav1+/+, PKA was colocalized with caveolin-1 in the cell membrane, but PKA immunoreactivity persisted in cav1−/−. Examination of PKA expression in the lipid raft-rich membrane fraction of the jejunum revealed reduced PKA expression in cav1−/− compared with cav1+/+. The results of the present study show that the function of β-adrenoceptors is reduced in cav1−/− small intestine likely owing to reduced PKA activity.

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Rathor, Navneeta, Ran Zhuang, Jian-Ying Wang, James M. Donahue, Douglas J. Turner, and Jaladanki N. Rao. "Src-mediated caveolin-1 phosphorylation regulates intestinal epithelial restitution by altering Ca2+ influx after wounding." American Journal of Physiology-Gastrointestinal and Liver Physiology 306, no. 8 (April 15, 2014): G650—G658. http://dx.doi.org/10.1152/ajpgi.00003.2014.

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Early mucosal restitution occurs as a consequence of intestinal epithelial cell (IEC) migration to reseal superficial wounds, but its exact mechanism remains largely unknown. Caveolin-1 (Cav1), a major component associated with caveolar lipid rafts in the plasma membrane, is implicated in many aspects of cellular functions. This study determined if c-Src kinase (Src)-induced Cav1 phosphorylation promotes intestinal epithelial restitution after wounding by activating Cav1-mediated Ca2+ signaling. Src directly interacted with Cav1, formed Cav1-Src complexes, and phosphorylated Cav1 in IECs. Inhibition of Src activity by its chemical inhibitor PP2 or suppression of the functional caveolin scaffolding domain by caveolin-scaffolding domain peptides prevented Cav1-Src interaction, reduced Cav1 phosphorylation, decreased Ca2+ influx, and inhibited cell migration after wounding. Disruption of caveolar lipid raft microdomains by methyl-β-cyclodextrin reduced Cav1-mediated Ca2+ influx and repressed epithelial restitution. Moreover, Src silencing prevented subcellular redistribution of phosphorylated Cav1 in migrating IECs. These results indicate that Src-induced Cav1 phosphorylation stimulates epithelial restitution by increasing Cav1-mediated Ca2+ signaling after wounding, thus contributing to the maintenance of gut mucosal integrity under various pathological conditions.

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Geletu, Mulu, Zaid Taha, Rozanne Arulanandam, Reva Mohan, Hikmat H. Assi, Maria G. Castro, Ivan Robert Nabi, Patrick T. Gunning, and Leda Raptis. "Effect of caveolin-1 on Stat3-ptyr705 levels in breast and lung carcinoma cells." Biochemistry and Cell Biology 97, no. 5 (October 2019): 638–46. http://dx.doi.org/10.1139/bcb-2018-0367.

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We recently demonstrated that Cav1 (caveolin-1) is a negative regulator of Stat3 (signal transducer and activator of transcription-3) activity in mouse fibroblasts and human lung carcinoma SHP77 cells. We now examined whether the cellular context may affect their levels as well as the relationship between them, by assessing Cav1 and Stat3-ptyr705 amounts in different cell lines. In MDA-MB-231, A549, and HaCat cells, Cav1 levels were high and Stat3-ptyr705 levels were low, consistent with the notion of a negative effect of endogenous Cav1 on Stat3-ptyr705 levels in these lines. In addition, manipulation of Cav1 levels revealed a negative effect in MCF7 and mouse fibroblast cells, while Cav1 upregulation induced apoptosis in MCF7 cells. In contrast, however, line MRC9 had high Cav1 and high Stat3-ptyr705 levels, indicating that high Cav1 is insufficient to reduce Stat3-ptyr705 levels in this line. MCF7 and LuCi6 cells had very low Cav1 and Stat3-ptyr705 levels, indicating that the low Stat3-ptyr705 can be independent from Cav1 levels altogether. Our results reveal a further level of complexity in the relationship between Cav1 and Stat3-ptyr705 than previously thought. In addition, we demonstrate that in a feedback loop, Stat3 inhibition upregulates Cav1 in HeLa cells but not in other lines tested.

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Godina, Christopher, Somayeh Khazaei, Mattias Belting, Johan Vallon-Christersson, Björn Nodin, Karin Jirström, Karolin Isaksson, Ana Bosch, and Helena Jernström. "Abstract A006: Spatial localization of Caveolin-1 protein in triple negative breast cancer is related to different molecular features." Cancer Research 84, no. 3_Supplement_1 (February 1, 2024): A006. http://dx.doi.org/10.1158/1538-7445.advbc23-a006.

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Abstract Background: Triple negative breast cancer (TNBC) is an aggressive and heterogeneous form of breast cancer with few targeted therapies and clinically used biomarkers. Caveolin-1 (CAV1) is a marker of stromal activation and vascularization. Molecular features of the tumor microenvironment (TME), important for tumor metastasis, may improve precision oncology in TNBC. CAV1 protein levels have previously been reported as a potential biomarker in breast cancer depending on their localization. Therefore, we aimed to investigate CAV1 protein levels in malignant and stromal cells of TNBC and their relation to CAV1 gene expression, clinicopathological factors, and molecular features. Methods: Tumor-specific CAV1 protein levels were evaluated with immunohistochemistry in malignant and stromal cells in tumor tissue microarrays from a cohort of 242 TNBC patients (inclusion 2010-2015, Sweden) from SCAN-B (NCT03758976). The protein levels of CAV1 in malignant and stromal cells were dichotomized as ‘strong’ (1) vs ‘negative to moderate’ (0) The CAV1 categories in malignant and stromal cells, respectively, were combined to create a joint CAV1 status with four categories: malignant/stromal cells, 0/0, 0/1, 1/0, and 1/1. Gene expression profiles from massive parallel paired-end sequencing of mRNA (RNA-seq) were available for all the tumors and from which PAM50 category and TNBC subtype were assigned. CAV1 status in malignant and stromal cells in relation to clinicopathological factors was analyzed using Chi-Square test. CAV1 mRNA expression in relation to CAV1 status in malignant and stromal cells was evaluated using Kruskal-Wallis test. Results: CAV1 status could be evaluated in 231/242 tumors. Strong CAV1 staining in malignant cells was associated with higher histological grade but no axillary lymph node involvement (both P <0.007). In contrast, strong CAV1 staining in stromal cells was associated with lower histological grade but axillary lymph node involvement (both P <0.001). Strong CAV1 staining in stromal cells was also associated with higher age at diagnosis (P =0.025). With regards to PAM50 subtypes, CAV1 in malignant cells was positively associated with the basal subtype while CAV1 in malignant cells was positively associated with the HER2 enriched subtype (P <0.001). Depending on localization, CAV1 expression was associated with different TNBCsubtypes. CAV1 in malignant cells was positively associated with the mesenchymal and negatively associated with the immunomodulatory subtype (P <0.001). CAV1 in stromal cells was positively associated with the luminal androgen (LAR) subtype (P <0.001). Neither CAV1 protein levels in malignant cells nor in stromal cells were correlated with CAV1 gene expression in the tumors, and the combined CAV1 status was not associated with CAV1 gene expression. Conclusion: CAV1 protein levels in malignant cells were related to different molecular features of TNBC compared to CAV1 protein levels in stromal cells. The results suggest that depending on localization, CAV1 protein levels function as two distinct biomarkers. Citation Format: Christopher Godina, Somayeh Khazaei, Mattias Belting, Johan Vallon-Christersson, Björn Nodin, Karin Jirström, Karolin Isaksson, Ana Bosch, Helena Jernström. Spatial localization of Caveolin-1 protein in triple negative breast cancer is related to different molecular features [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A006.

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Joshi, Bharat, Michele Bastiani, Scott S. Strugnell, Cecile Boscher, Robert G. Parton, and Ivan R. Nabi. "Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation." Journal of Cell Biology 199, no. 3 (October 22, 2012): 425–35. http://dx.doi.org/10.1083/jcb.201207089.

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Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase-dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin-dependent mechanotransduction and inactivation of the Egr1 (early growth response-1) transcription factor, relieving inhibition of endogenous Cav1 and cavin-1 genes. Cav1 phosphorylation reduces Egr1 binding to Cav1 and cavin-1 promoters and stimulates their activity. In MDA-231 breast carcinoma cells that express elevated levels of Cav1 and caveolae, Egr1 regulated Cav1, and cavin-1 promoter activity was dependent on actin, Cav1, Src, and Rho-associated kinase as well as downstream protein kinase C (PKC) signaling. pCav1 is therefore a mechanotransducer that acts via PKC to relieve Egr1 transcriptional inhibition of Cav1 and cavin-1, defining a novel feedback regulatory loop to regulate caveola biogenesis.

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Tang, Wenqing, Xuemei Feng, Si Zhang, Zhenggang Ren, Yinkun Liu, Biwei Yang, Bei lv, Yu Cai, Jinglin Xia, and Ningling Ge. "Caveolin-1 Confers Resistance of Hepatoma Cells to Anoikis by Activating IGF-1 Pathway." Cellular Physiology and Biochemistry 36, no. 3 (2015): 1223–36. http://dx.doi.org/10.1159/000430292.

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Background/Aims: Anoikis resistance is a prerequisite for hepatocellular carcinoma (HCC) metastasis. The role of Caveolin-1 (CAV1) in anoikis resistance of HCC remains unclear. Methods: The oncogenic effect of CAV1 on anchor-independent growth and anoikis resistance was investigated by overexpression and knockdown of CAV1 in hepatoma cells. IGF-1 pathway and its downstream signals were detected by immunoblot analysis. Caveolae invagination and IGF-1R internalization was studied by electron microscopy and 125I-IGF1 internalization assay, respectively. The role of IGF-1R and tyrosine-14 residue (Y-14) of CAV1 was explored by deletion experiment and mutation experiment, respectively. The correlation of CAV1 and IGF-1R was further examined by immunochemical analysis in 120 HCC specimens. Results: CAV1 could promote anchor-independent growth and anoikis resistance in hepatoma cells. CAV1-overexpression increased the expression of IGF-1R and subsequently activated PI3K/Akt and RAF/MEK/ERK pathway, while CAV1 knockdown showed the opposite effect. The mechanism study revealed that CAV1 facilitated caveolae invagination and 125I-IGF1 internalization. IGF-1R deletion or Y-14 mutation reversed CAV1 mediated anchor-independent growth and anoikis resistance. In addition, CAV1 expression was positively related to IGF-1R expression in human HCC tissues. Conclusion: CAV1 confers resistance of hepatoma cells to anoikis by activating IGF-1 pathway, providing a potential therapeutic target for HCC metastasis.

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Feldman, Rebecca, Zoran Gatalica, Sandeep K. Reddy, Michael Castro, and Jasgit C. Sachdev. "Caveolin-1: Oncogenic role in breast cancer? Clues from molecular profiling." Journal of Clinical Oncology 33, no. 28_suppl (October 1, 2015): 134. http://dx.doi.org/10.1200/jco.2015.33.28_suppl.134.

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134 Background: Caveolin-1 (CAV1) is the structural component of caveolae, compartments within the plasma membrane that sequester signaling molecules, thus facilitating molecular “hot spots”. The role of CAV1 in breast cancer is an active area of investigation. We sought to understand the clinical and pathological characteristics of CAV1 positive tumors (CAV 1+) through a retrospective analysis of molecularly-profiled breast cancer patients. Methods: 2,728 breast cancer patients molecularly profiled with a commercial assay (Caris Life Sciences) were evaluated retrospectively for expression of various biomarkers by immunohistochemistry (IHC) and in situ hybridization. JMP statistical analysis tool was used to ascertain distributional differences. Results: Using a threshold of 2+ and 30%, 121/2728 (4%) of patients exhibited CAV1 over-expression by IHC. To observe clinicopathologic differences in the CAV1 + and CAV1- tumors, distribution by age, metastatic disease, and triple negative histology (TNBC) were analyzed. Average age for both groups was 55. 39% vs. 54% were metastatic and 74% vs. 26% were TNBC (p = 0.0001) among CAV1+ and CAV1- groups, respectively. To evaluate the potential oncogenic associations of CAV1, we evaluated the relationship between CAV1+ and various oncogenic pathways. Positive EGFR protein expression and presence of EGFR gene amplification, as well as cKIT over-expression associated with CAV1+ (all p-values < 0.001), whereas HER2 expression and amplification were associated with CAV1- (p = 0.001 for both). In addition, higher Ki67, p53 and TOP2A expression by IHC were observed in CAV1+ patients compared to the CAV1- subgroup (90% vs. 66%, 50% vs. 36%, 84% vs. 65% ; all p-values < 0.0001). Biomarker expression differences that did not meet statistical significance: ERCC1, MGMT, PDGFRA, RRM1, SPARC, TS and TOPO1. Conclusions: The majority of CAV1+ breast cancers are comprised of triple negative, higher proliferative tumors, with aberrant p53 expression as well as expression of other growth factor signaling proteins. This data supports the potential role of CAV1 in fostering molecular hubs for signaling and CAV-1 being a potential target for future therapeutic investigation in TNBC.

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Cai, Ting, Haojie Wang, Yiliang Chen, Lijun Liu, William T. Gunning, Luis Eduardo M. Quintas, and Zi-Jian Xie. "Regulation of caveolin-1 membrane trafficking by the Na/K-ATPase." Journal of Cell Biology 182, no. 6 (September 15, 2008): 1153–69. http://dx.doi.org/10.1083/jcb.200712022.

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Here, we show that the Na/K-ATPase interacts with caveolin-1 (Cav1) and regulates Cav1 trafficking. Graded knockdown of Na/K-ATPase decreases the plasma membrane pool of Cav1, which results in a significant reduction in the number of caveolae on the cell surface. These effects are independent of the pumping function of Na/K-ATPase, and instead depend on interaction between Na/K-ATPase and Cav1 mediated by an N-terminal caveolin-binding motif within the ATPase α1 subunit. Moreover, knockdown of the Na/K-ATPase increases basal levels of active Src and stimulates endocytosis of Cav1 from the plasma membrane. Microtubule-dependent long-range directional trafficking in Na/K-ATPase–depleted cells results in perinuclear accumulation of Cav1-positive vesicles. Finally, Na/K-ATPase knockdown has no effect on processing or exit of Cav1 from the Golgi. Thus, the Na/K-ATPase regulates Cav1 endocytic trafficking and stabilizes the Cav1 plasma membrane pool.

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Avchalumov, Yosef, Alison D. Kreisler, Wulfran Trenet, Mahasweta Nayak, Brian P. Head, Juan C. Piña-Crespo, and Chitra D. Mandyam. "Caveolin-1 Expression in the Dorsal Striatum Drives Methamphetamine Addiction-Like Behavior." International Journal of Molecular Sciences 22, no. 15 (July 30, 2021): 8219. http://dx.doi.org/10.3390/ijms22158219.

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Dopamine D1 receptor (D1R) function is regulated by membrane/lipid raft-resident protein caveolin-1 (Cav1). We examined whether altered expression of Cav1 in the dorsal striatum would affect self-administration of methamphetamine, an indirect agonist at the D1Rs. A lentiviral construct expressing Cav1 (LV-Cav1) or containing a short hairpin RNA against Cav1 (LV-shCav1) was used to overexpress or knock down Cav1 expression respectively, in the dorsal striatum. Under a fixed-ratio schedule, LV-Cav1 enhanced and LV-shCav1 reduced responding for methamphetamine in an extended access paradigm compared to LV-GFP controls. LV-Cav1 and LV-shCav1 also produced an upward and downward shift in a dose–response paradigm, generating a drug vulnerable/resistant phenotype. LV-Cav1 and LV-shCav1 did not alter responding for sucrose. Under a progressive-ratio schedule, LV-shCav1 generally reduced positive-reinforcing effects of methamphetamine and sucrose as seen by reduced breakpoints. Western blotting confirmed enhanced Cav1 expression in LV-Cav1 rats and reduced Cav1 expression in LV-shCav1 rats. Electrophysiological findings in LV-GFP rats demonstrated an absence of high-frequency stimulation (HFS)-induced long-term potentiation (LTP) in the dorsal striatum after extended access methamphetamine self-administration, indicating methamphetamine-induced occlusion of plasticity. LV-Cav1 prevented methamphetamine-induced plasticity via increasing phosphorylation of calcium calmodulin kinase II, suggesting a mechanism for addiction vulnerability. LV-shCav1 produced a marked deficit in the ability of HFS to produce LTP and, therefore, extended access methamphetamine was unable to alter striatal plasticity, indicating a mechanism for resistance to addiction-like behavior. Our results demonstrate that Cav1 expression and knockdown driven striatal plasticity assist with modulating addiction to drug and nondrug rewards, and inspire new strategies to reduce psychostimulant addiction.

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Godina, Christopher, Somayeh Khazaei, Mattias Belting, Johan Vallon-Christersson, Björn Nodin, Karin Jirström, Karolin Isaksson, Ana Bosch, and Helena Jernström. "High Caveolin-1 mRNA expression in triple-negative breast cancer is associated with an aggressive tumor microenvironment, chemoresistance, and poor clinical outcome." PLOS ONE 19, no. 7 (July 3, 2024): e0305222. http://dx.doi.org/10.1371/journal.pone.0305222.

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Background Currently, there are few treatment-predictive and prognostic biomarkers in triple-negative breast cancer (TNBC). Caveolin-1 (CAV1) is linked to chemoresistance and several important processes involved in tumor progression and metastasis, such as epithelial-mesenchymal transition (EMT). Herein, we report that high CAV1 gene expression is an independent factor of poor prognosis in TNBC. Methods CAV1 gene expression was compared across different molecular features (e.g., PAM50 subtypes). CAV1 expression was assessed in relation to clinical outcomes using Cox regression adjusted for clinicopathological predictors. Differential gene expression and gene set enrichment analyses were applied to compare high- and low-expressing CAV1 tumors. Tumor microenvironment composition of high- and low-expressing CAV1 tumors was estimated using ECOTYPER. Tumor tissue microarrays were used to evaluate CAV1 protein levels in stromal and malignant cells. Results In the SCAN-B (n = 525) and GSE31519 (n = 327) cohorts, patients with CAV1-high tumors had an increased incidence of early recurrence adjusted HR 1.78 (95% CI 1.12–2.81) and 2.20 (95% CI 1.39–3.47), respectively. In further analysis, high CAV1 gene expression was associated with a molecular profile indicating altered metabolism, neovascularization, chemoresistance, EMT, suppressed immune response, and active tumor microenvironment. Protein levels of CAV1 in malignant and stromal cells were not correlated with CAV1 gene expression. Conclusion CAV1 gene expression in TNBC is a biomarker that merits further investigation in clinical trials and as a therapeutic target.

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Zimnicka, Adriana M., Yawer S. Husain, Ayesha N. Shajahan, Maria Sverdlov, Oleg Chaga, Zhenlong Chen, Peter T. Toth, et al. "Src-dependent phosphorylation of caveolin-1 Tyr-14 promotes swelling and release of caveolae." Molecular Biology of the Cell 27, no. 13 (July 2016): 2090–106. http://dx.doi.org/10.1091/mbc.e15-11-0756.

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Caveolin 1 (Cav1) is a required structural component of caveolae, and its phosphorylation by Src is associated with an increase in caveolae-mediated endocytosis. Here we demonstrate, using quantitative live-cell 4D, TIRF, and FRET imaging, that endocytosis and trafficking of caveolae are associated with a Cav1 Tyr-14 phosphorylation-dependent conformational change, which spatially separates, or loosens, Cav1 molecules within the oligomeric caveolar coat. When tracked by TIRF and spinning-disk microscopy, cells expressing phosphomimicking Cav1 (Y14D) mutant formed vesicles that were greater in number and volume than with Y14F-Cav1-GFP. Furthermore, we observed in HEK cells cotransfected with wild-type, Y14D, or Y14F Cav1-CFP and -YFP constructs that FRET efficiency was greater with Y14F pairs than with Y14D, indicating that pY14-Cav1 regulates the spatial organization of Cav1 molecules within the oligomer. In addition, albumin-induced Src activation or direct activation of Src using a rapamycin-inducible Src construct (RapR-Src) led to an increase in monomeric Cav1 in Western blots, as well as a simultaneous increase in vesicle number and decrease in FRET intensity, indicative of a Src-mediated conformational change in CFP/YFP-tagged WT-Cav1 pairs. We conclude that phosphorylation of Cav1 leads to separation or “spreading” of neighboring negatively charged N-terminal phosphotyrosine residues, promoting swelling of caveolae, followed by their release from the plasma membrane.

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Al Madhoun, Ashraf, Shihab Kochumon, Dania Haddad, Reeby Thomas, Rasheeba Nizam, Lavina Miranda, Sardar Sindhu, Milad S. Bitar, Rasheed Ahmad, and Fahd Al-Mulla. "Adipose Tissue Caveolin-1 Upregulation in Obesity Involves TNF-α/NF-κB Mediated Signaling." Cells 12, no. 7 (March 27, 2023): 1019. http://dx.doi.org/10.3390/cells12071019.

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Obesity is characterized by chronic low-grade inflammation. Obese people have higher levels of caveolin-1 (CAV1), a structural and functional protein present in adipose tissues (ATs). We aimed to define the inflammatory mediators that influence CAV1 gene regulation and the associated mechanisms in obesity. Using subcutaneous AT from 27 (7 lean and 20 obese) normoglycemic individuals, in vitro human adipocyte models, and in vivo mice models, we found elevated CAV1 expression in obese AT and a positive correlation between the gene expression of CAV1, tumor necrosis factor-alpha (TNF-α), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). CAV1 gene expression was associated with proinflammatory cytokines and chemokines and their cognate receptors (r ≥ 0.447, p ≤ 0.030), but not with anti-inflammatory markers. CAV1 expression was correlated with CD163, indicating a prospective role for CAV1 in the adipose inflammatory microenvironment. Unlike wild-type animals, mice lacking TNF-α exhibited reduced levels of CAV1 mRNA/proteins, which were elevated by administering exogenous TNF-α. Mechanistically, TNF-α induces CAV1 gene transcription by mediating NF-κB binding to its two regulatory elements located in the CAV1 proximal regulatory region. The interplay between CAV1 and the TNF-α signaling pathway is intriguing and has potential as a target for therapeutic interventions in obesity and metabolic syndromes.

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Lobos-González, Lorena, Lorena Oróstica, Natalia Díaz-Valdivia, Victoria Rojas-Celis, America Campos, Eduardo Duran-Jara, Nicole Farfán, Lisette Leyton, and Andrew F. G. Quest. "Prostaglandin E2 Exposure Disrupts E-Cadherin/Caveolin-1-Mediated Tumor Suppression to Favor Caveolin-1-Enhanced Migration, Invasion, and Metastasis in Melanoma Models." International Journal of Molecular Sciences 24, no. 23 (November 29, 2023): 16947. http://dx.doi.org/10.3390/ijms242316947.

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Caveolin-1 (CAV1) is a membrane-bound protein that suppresses tumor development yet also promotes metastasis. E-cadherin is important in CAV1-dependent tumor suppression and prevents CAV1-enhanced lung metastasis. Here, we used murine B16F10 and human A375 melanoma cells with low levels of endogenous CAV1 and E-cadherin to unravel how co-expression of E-cadherin modulates CAV1 function in vitro and in vivo in WT C57BL/6 or Rag−/− immunodeficient mice and how a pro-inflammatory environment generated by treating cells with prostaglandin E2 (PGE2) alters CAV1 function in the presence of E-cadherin. CAV1 expression augmented migration, invasion, and metastasis of melanoma cells, and these effects were abolished via transient co-expression of E-cadherin. Importantly, exposure of cells to PGE2 reverted the effects of E-cadherin expression and increased CAV1 phosphorylation on tyrosine-14 and metastasis. Moreover, PGE2 administration blocked the ability of the CAV1/E-cadherin complex to prevent tumor formation. Therefore, our results support the notion that PGE2 can override the tumor suppressor potential of the E-cadherin/CAV1 complex and that CAV1 released from the complex is phosphorylated on tyrosine-14 and promotes migration/invasion/metastasis. These observations provide direct evidence showing how a pro-inflammatory environment caused here via PGE2 administration can convert a potent tumor suppressor complex into a promoter of malignant cell behavior.

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Gairhe, Salina, Keytam S. Awad, Edward J. Dougherty, Gabriela A. Ferreyra, Shuibang Wang, Zu-Xi Yu, Kazuyo Takeda, et al. "Type I interferon activation and endothelial dysfunction in caveolin-1 insufficiency-associated pulmonary arterial hypertension." Proceedings of the National Academy of Sciences 118, no. 11 (March 8, 2021): e2010206118. http://dx.doi.org/10.1073/pnas.2010206118.

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Interferonopathies, interferon (IFN)-α/β therapy, and caveolin-1 (CAV1) loss-of-function have all been associated with pulmonary arterial hypertension (PAH). Here, CAV1-silenced primary human pulmonary artery endothelial cells (PAECs) were proliferative and hypermigratory, with reduced cytoskeletal stress fibers. Signal transducers and activators of transcription (STAT) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) were both constitutively activated in these cells, resulting in a type I IFN-biased inflammatory signature. Cav1−/− mice that spontaneously develop pulmonary hypertension were found to have STAT1 and AKT activation in lung homogenates and increased circulating levels of CXCL10, a hallmark of IFN-mediated inflammation. PAH patients with CAV1 mutations also had elevated serum CXCL10 levels and their fibroblasts mirrored phenotypic and molecular features of CAV1-deficient PAECs. Moreover, immunofluorescence staining revealed endothelial CAV1 loss and STAT1 activation in the pulmonary arterioles of patients with idiopathic PAH, suggesting that this paradigm might not be limited to rare CAV1 frameshift mutations. While blocking JAK/STAT or AKT rescued aspects of CAV1 loss, only AKT inhibitors suppressed activation of both signaling pathways simultaneously. Silencing endothelial nitric oxide synthase (NOS3) prevented STAT1 and AKT activation induced by CAV1 loss, implicating CAV1/NOS3 uncoupling and NOS3 dysregulation in the inflammatory phenotype. Exogenous IFN reduced CAV1 expression, activated STAT1 and AKT, and altered the cytoskeleton of PAECs, implicating these mechanisms in PAH associated with autoimmune and autoinflammatory diseases, as well as IFN therapy. CAV1 insufficiency elicits an IFN inflammatory response that results in a dysfunctional endothelial cell phenotype and targeting this pathway may reduce pathologic vascular remodeling in PAH.

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Zhang, Chengbiao, Xiaotong Su, Lars Bellner, and Dao-Hong Lin. "Caveolin-1 regulates corneal wound healing by modulating Kir4.1 activity." American Journal of Physiology-Cell Physiology 310, no. 11 (June 1, 2016): C993—C1000. http://dx.doi.org/10.1152/ajpcell.00023.2016.

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The expression of caveolin-1 (Cav1) in corneal epithelium is associated with regeneration potency. We used Cav1−/− mice to study the role of Cav1 in modulating corneal wound healing. Western blot and whole cell patch clamp were employed to study the effect of Cav1 deletion on Kir4.1 current density in corneas. We found that Ba2+-sensitive K+ currents in primary cultured murine corneal epithelial cells (pMCE) from Cav1−/− were dramatically reduced (602 pA) compared with those from wild type (WT; 1,300 pA). As a consequence, membrane potential was elevated in pMCE from Cav1−/− compared with that from WT (−43 ± 7.5 vs. −58 ± 4.0 mV, respectively). Western blot showed that either inhibition of Cav1 expression or Ba2+ incubation stimulated phosphorylation of the EGFR. The transwell migration assay showed that Cav1 genetic inactivation accelerated cell migration. The regrowth efficiency of human corneal epithelial cells (HCE) transfected with siRNA-Cav1 or negative control was evaluated by scrape injury assay. With the presence of mitomycin C (10 μg/ml) to avoid the influence of cell proliferation, Cav1 inhibition with siRNA significantly increased migration compared with control siRNA in HCE. This promoting effect by siRNA-Cav1 could not be further enhanced by cotransfection with siRNA-Kcnj10. By using corneal debridement, we found that wound healing was significantly accelerated in Cav1−/− compared with WT mice (70 ± 10 vs. 36 ± 3%, P < 0.01). Our findings imply that the mechanism by which Cav-1 knockout promotes corneal regrowth is, at least partially, due to the inhibition of Kir4.1 which stimulates EGFR signaling.

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Journal articles on the topic 'CaVβ1'

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