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1
Dvorak, Nolan M., Paul A. Wadsworth, Pingyuan Wang, Jia Zhou e Fernanda Laezza. "Development of Allosteric Modulators of Voltage-Gated Na+ Channels: A Novel Approach for an Old Target". Current Topics in Medicinal Chemistry 21, n. 10 (17 giugno 2021): 841–48. http://dx.doi.org/10.2174/1568026621666210525105359.
Abstract (sommario):
Given their primacy in governing the action potential (AP) of excitable cells, voltage-gated Na+ (Nav) channels are important pharmacological targets of therapeutics for a diverse array of clinical indications. Despite historically being a traditional drug target, therapeutics targeting Nav channels lack isoform selectivity, giving rise to off-target side effects. To develop isoform-selective modulators of Nav channels with improved target-specificity, the identification and pharmacological targeting of allosteric sites that display structural divergence among Nav channel isoforms represents an attractive approach. Despite the high homology among Nav channel α subunit isoforms (Nav1.1-Nav1.9), there is considerable amino acid sequence divergence among their constituent C-terminal domains (CTD), which enables structurally and functionally specific protein: protein interactions (PPI) with auxiliary proteins. Although pharmacological targeting of such PPI interfaces between the CTDs of Nav channels and auxiliary proteins represents an innovate approach for developing isoform-selective modulators of Nav channels, appreciable modulation of PPIs using small molecules has conventionally been difficult to achieve. After briefly discussing the challenges of modulating PPIs using small molecules, this current frontier review that follows subsequently expounds on approaches for circumventing such difficulties in the context of developing small molecule modulators of PPIs between transmembrane ion channels and their auxiliary proteins. In addition to broadly discussing such approaches, the implementation of such approaches is specifically discussed in the context of developing small molecule modulators between the CTD of Nav channels and auxiliary proteins. Developing allosteric modulators of ion channels by targeting their PPI interfaces with auxiliary proteins represents an innovative and promising strategy in ion channel drug discovery that could expand the “druggable genome” and usher in first-in-class PPI-targeting therapeutics for a multitude of channelopathies.
2
Flockerzi, Veit, e Bernd Fakler. "TR(i)P Goes On: Auxiliary TRP Channel Subunits?" Circulation Research 134, n. 4 (16 febbraio 2024): 346–50. http://dx.doi.org/10.1161/circresaha.123.323178.
Abstract (sommario):
Transient receptor potential (TRP) cation channels are a diverse family of channels whose members play prominent roles as cellular sensors and effectors. The important role of TRP channels (and mechanosensitive piezo channels) in the complex interaction of our senses with the environment was underlined by the award of the Nobel Prize in Physiology or Medicine to 2 pioneers in this field, David Julius and Ardem Patapoutian. There are many competent and comprehensive reviews on many aspects of the TRP channels, and there is no intention to expand on them. Rather, after an introduction to the nomenclature, the molecular architecture of native TRP channel/protein complexes in vivo will be summarized using TRP channels of the canonical transient receptor potential subfamily as an example. This molecular architecture provides the basis for the signatures of native canonical transient receptor potential currents and their control by endogenous modulators and potential drugs.
3
Hoshi, Toshinori, Rong Xu, Shangwei Hou, Stefan H. Heinemann e Yutao Tian. "A point mutation in the human Slo1 channel that impairs its sensitivity to omega-3 docosahexaenoic acid". Journal of General Physiology 142, n. 5 (14 ottobre 2013): 507–22. http://dx.doi.org/10.1085/jgp.201311061.
Abstract (sommario):
Long-chain polyunsaturated omega-3 fatty acids such as docosahexaenoic acid (DHA) at nanomolar concentrations reversibly activate human large-conductance Ca2+- and voltage-gated K+ (Slo1 BK) channels containing auxiliary β1 or β4 subunits in cell-free patches. Here we examined the action of DHA on the Slo1 channel without any auxiliary subunit and sought to elucidate the biophysical mechanism and the molecular determinants of the DHA sensitivity. Measurements of ionic currents through human Slo1 (hSlo1) channels reveal that the stimulatory effect of DHA does not require activation of the voltage or Ca2+ sensors. Unlike gating of the hSlo1 channel, that of the Drosophila melanogaster Slo1 (dSlo1) channel is unaltered by DHA. Our mutagenesis study based on the differential responses of human and dSlo1 channels to DHA pinpoints that Y318 near the cytoplasmic end of S6 in the hSlo1 channel is a critical determinant of the stimulatory action of DHA. The mutation Y318S in hSlo1, which replaces Y with S as found in dSlo1, greatly diminishes the channel’s response to DHA with a 22-carbon chain whether β1 or β4 is absent or present. However, the responses to α-linolenic acid, an omegea-3 fatty acid with an 18-carbon chain, and to arachidonic acid, an omega-6 fatty acid with a 20-carbon chain, remain unaffected by the mutation. Y318 in the S6 segment of hSlo1 is thus an important determinant of the electrophysiological response of the channel to DHA. Furthermore, the mutation Y318S may prove to be useful in dissecting out the complex lipid-mediated modulation of Slo1 BK channels.
4
Zhou, Zijing, Xiaonuo Ma, Yiechang Lin, Delfine Cheng, Navid Bavi, Genevieve A. Secker, Jinyuan Vero Li et al. "MyoD-family inhibitor proteins act as auxiliary subunits of Piezo channels". Science 381, n. 6659 (18 agosto 2023): 799–804. http://dx.doi.org/10.1126/science.adh8190.
Abstract (sommario):
Piezo channels are critical cellular sensors of mechanical forces. Despite their large size, ubiquitous expression, and irreplaceable roles in an ever-growing list of physiological processes, few Piezo channel–binding proteins have emerged. In this work, we found that MyoD (myoblast determination)–family inhibitor proteins (MDFIC and MDFI) are PIEZO1/2 interacting partners. These transcriptional regulators bind to PIEZO1/2 channels, regulating channel inactivation. Using single-particle cryogenic electron microscopy, we mapped the interaction site in MDFIC to a lipidated, C-terminal helix that inserts laterally into the PIEZO1 pore module. These Piezo-interacting proteins fit all the criteria for auxiliary subunits, contribute to explaining the vastly different gating kinetics of endogenous Piezo channels observed in many cell types, and elucidate mechanisms potentially involved in human lymphatic vascular disease.
5
Jones, Lisa P., Shao-kui Wei e David T. Yue. "Mechanism of Auxiliary Subunit Modulation of Neuronal α1E Calcium Channels". Journal of General Physiology 112, n. 2 (1 agosto 1998): 125–43. http://dx.doi.org/10.1085/jgp.112.2.125.
Abstract (sommario):
Voltage-gated calcium channels are composed of a main pore-forming α1 moiety, and one or more auxiliary subunits (β, α2δ) that modulate channel properties. Because modulatory properties may vary greatly with different channels, expression systems, and protocols, it is advantageous to study subunit regulation with a uniform experimental strategy. Here, in HEK 293 cells, we examine the expression and activation gating of α1E calcium channels in combination with a β (β1–β4) and/or the α2δ subunit, exploiting both ionic- and gating-current measurements. Furthermore, to explore whether more than one auxiliary subunit can concomitantly specify gating properties, we investigate the effects of cotransfecting α2δ with β subunits, of transfecting two different β subunits simultaneously, and of COOH-terminal truncation of α1E to remove a second β binding site. The main results are as follows. (a) The α2δ and β subunits modulate α1E in fundamentally different ways. The sole effect of α2δ is to increase current density by elevating channel density. By contrast, though β subunits also increase functional channel number, they also enhance maximum open probability (Gmax/Qmax) and hyperpolarize the voltage dependence of ionic-current activation and gating-charge movement, all without discernible effect on activation kinetics. Different β isoforms produce nearly indistinguishable effects on activation. However, β subunits produced clear, isoform-specific effects on inactivation properties. (b) All the β subunit effects can be explained by a gating model in which subunits act only on weakly voltage-dependent steps near the open state. (c) We find no clear evidence for simultaneous modulation by two different β subunits. (d) The modulatory features found here for α1E do not generalize uniformly to other α1 channel types, as α1C activation gating shows marked β isoform dependence that is absent for α1E. Together, these results help to establish a more comprehensive picture of auxiliary-subunit regulation of α1E calcium channels.
6
Jiao, Yunjing, Qijing Lin, Kun Yao, Na Zhao, Dan Xian, Fuzheng Zhang, Qingzhi Meng, Bian Tian e Zhuangde Jiang. "Design of High-Precision Parallel AWG Demodulation System". Micromachines 14, n. 9 (25 agosto 2023): 1662. http://dx.doi.org/10.3390/mi14091662.
Abstract (sommario):
Here, we present a high-precision demodulation method that supports the arrayed waveguide grating (AWG) system, which includes a 1 × 8 AWG as the primary filter with a 0.5 nm channel spacing and a 1 × 4 AWG as the auxiliary filter with a 1 nm channel spacing. The high precision is achieved through an innovative method of decoupling three channels, involving two adjacent channels of the primary filter and one channel of the secondary auxiliary filter. Simulation results show that the AWGs have a good transmission spectrum with crosstalk below −24.8 dB, non-uniformities below 0.8 dB, insertion loss below −3.7 dB, 3 dB bandwidth of 0.25 nm, and 10 dB bandwidth of 0.43 nm. The interrogation precision can reach 8 pm, with a dynamic range of 0.4 nm, corresponding to a single FBG.
7
Dvorak, Nolan M., Cynthia M. Tapia, Aditya K. Singh, Timothy J. Baumgartner, Pingyuan Wang, Haiying Chen, Paul A. Wadsworth, Jia Zhou e Fernanda Laezza. "Pharmacologically Targeting the Fibroblast Growth Factor 14 Interaction Site on the Voltage-Gated Na+ Channel 1.6 Enables Isoform-Selective Modulation". International Journal of Molecular Sciences 22, n. 24 (17 dicembre 2021): 13541. http://dx.doi.org/10.3390/ijms222413541.
Abstract (sommario):
Voltage-gated Na+ (Nav) channels are the primary molecular determinant of the action potential. Among the nine isoforms of the Nav channel α subunit that have been described (Nav1.1-Nav1.9), Nav1.1, Nav1.2, and Nav1.6 are the primary isoforms expressed in the central nervous system (CNS). Crucially, these three CNS Nav channel isoforms display differential expression across neuronal cell types and diverge with respect to their subcellular distributions. Considering these differences in terms of their localization, the CNS Nav channel isoforms could represent promising targets for the development of targeted neuromodulators. However, current therapeutics that target Nav channels lack selectivity, which results in deleterious side effects due to modulation of off-target Nav channel isoforms. Among the structural components of the Nav channel α subunit that could be pharmacologically targeted to achieve isoform selectivity, the C-terminal domains (CTD) of Nav channels represent promising candidates on account of displaying appreciable amino acid sequence divergence that enables functionally unique protein–protein interactions (PPIs) with Nav channel auxiliary proteins. In medium spiny neurons (MSNs) of the nucleus accumbens (NAc), a critical brain region of the mesocorticolimbic circuit, the PPI between the CTD of the Nav1.6 channel and its auxiliary protein fibroblast growth factor 14 (FGF14) is central to the generation of electrical outputs, underscoring its potential value as a site for targeted neuromodulation. Focusing on this PPI, we previously developed a peptidomimetic derived from residues of FGF14 that have an interaction site on the CTD of the Nav1.6 channel. In this work, we show that whereas the compound displays dose-dependent effects on the activity of Nav1.6 channels in heterologous cells, the compound does not affect Nav1.1 or Nav1.2 channels at comparable concentrations. In addition, we show that the compound correspondingly modulates the action potential discharge and the transient Na+ of MSNs of the NAc. Overall, these results demonstrate that pharmacologically targeting the FGF14 interaction site on the CTD of the Nav1.6 channel is a strategy to achieve isoform-selective modulation, and, more broadly, that sites on the CTDs of Nav channels interacted with by auxiliary proteins could represent candidates for the development of targeted therapeutics.
8
Sinha, Ashish, Haodong Gu, Namwoon Kim e Renu Emile. "Signaling effects and the role of culture: movies in international auxiliary channels". European Journal of Marketing 53, n. 10 (7 ottobre 2019): 2146–72. http://dx.doi.org/10.1108/ejm-09-2017-0587.
Abstract (sommario):
Purpose Given the high uncertainty in the quality perception of experiential products, manufacturers use signals to influence consumers’ decisions. In the movie industry, literature shows that performance of the main channel (e.g. cinema) strongly influences the performance of auxiliary channels (e.g. DVDs). The success of a movie in the home country is also to be resonated by its good performance in host countries. However, the cultural contingency of these success-breeds-success (SBS) effects has not been examined. This paper aims to test the influence of cultural values on the SBS effects across channels and countries. Design/methodology/approach Borrowing concepts from the signaling literature and analyzing DVD sales data from six international markets using a multilevel mixed-effects model, the study finds that culture plays a significant role to influence both SBS effects. Findings In countries with low power distance, short-term orientation and high indulgence, consumers who purchase from auxiliary channels are more likely to be influenced by the box office performance of movies. Meanwhile, cultural distance between the home and host nations significantly decreases the cross-national SBS effect. Research limitations/implications The findings are likely to be generalized to online auxiliary channels of movies, but empirical testing is required to ensure that no major adaptation is required in the process. Future research can also extend the framework of this paper to include more countries into the analysis and investigate cultural variables beyond Hofstede’s dimensions. Practical implications This paper suggests that the SBS effects may vary across nations. When managers plan for the sequential distributions of experiential products, the cultural values of target markets should be considered to decrease the uncertainty in sales prediction. Originality/value This paper contributes to the existing literature by investigating the international auxiliary channels of movies and incorporating cultural values into the framework of sequential distributions. To the best of the authors’ knowledge, this study is the first to test the links between the main and auxiliary channels from an international marketing perspective.
9
Brown, Austin L., Zhiwen Liao e Miriam B. Goodman. "MEC-2 and MEC-6 in the Caenorhabditis elegans Sensory Mechanotransduction Complex: Auxiliary Subunits that Enable Channel Activity". Journal of General Physiology 131, n. 6 (26 maggio 2008): 605–16. http://dx.doi.org/10.1085/jgp.200709910.
Abstract (sommario):
The ion channel formed by the homologous proteins MEC-4 and MEC-10 forms the core of a sensory mechanotransduction channel in Caenorhabditis elegans. Although the products of other mec genes are key players in the biophysics of transduction, the mechanism by which they contribute to the properties of the channel is unknown. Here, we investigate the role of two auxiliary channel subunits, MEC-2 (stomatin-like) and MEC-6 (paraoxonase-like), by coexpressing them with constitutively active MEC-4/MEC-10 heteromeric channels in Xenopus oocytes. This work extends prior work demonstrating that MEC-2 and MEC-6 synergistically increase macroscopic current. We use single-channel recordings and biochemistry to show that these auxiliary subunits alter function by increasing the number of channels in an active state rather than by dramatically affecting either single-channel properties or surface expression. We also use two-electrode voltage clamp and outside-out macropatch recording to examine the effects of divalent cations and proteases, known regulators of channel family members. Finally, we examine the role of cholesterol binding in the mechanism of MEC-2 action by measuring whole-cell and single-channel currents in MEC-2 mutants deficient in cholesterol binding. We suggest that MEC-2 and MEC-6 play essential roles in modulating both the local membrane environment of MEC-4/MEC-10 channels and the availability of such channels to be gated by force in vivo.
10
Williams, Brittany, Josue A. Lopez, J. Wesley Maddox e Amy Lee. "Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Cav1.4 Ca2+ channels". Journal of Biological Chemistry 295, n. 50 (8 ottobre 2020): 17215–26. http://dx.doi.org/10.1074/jbc.ra120.014138.
Abstract (sommario):
Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.
11
Dolphin, Annette C. "Voltage-gated calcium channels: Their discovery, function and importance as drug targets". Brain and Neuroscience Advances 2 (gennaio 2018): 239821281879480. http://dx.doi.org/10.1177/2398212818794805.
Abstract (sommario):
This review will first describe the importance of Ca2+ entry for function of excitable cells, and the subsequent discovery of voltage-activated calcium conductances in these cells. This finding was rapidly followed by the identification of multiple subtypes of calcium conductance in different tissues. These were initially termed low- and high-voltage activated currents, but were then further subdivided into L-, N-, PQ-, R- and T-type calcium currents on the basis of differing pharmacology, voltage-dependent and kinetic properties, and single channel conductance. Purification of skeletal muscle calcium channels allowed the molecular identification of the pore-forming and auxiliary α2δ, β and ϒ subunits present in these calcium channel complexes. These advances then led to the cloning of the different subunits, which permitted molecular characterisation, to match the cloned channels with physiological function. Studies with knockout and other mutant mice then allowed further investigation of physiological and pathophysiological roles of calcium channels. In terms of pharmacology, cardiovascular L-type channels are targets for the widely used antihypertensive 1,4-dihydropyridines and other calcium channel blockers, N-type channels are a drug target in pain, and α2δ-1 is the therapeutic target of the gabapentinoid drugs, used in neuropathic pain. Recent structural advances have allowed a deeper understanding of Ca2+ permeation through the channel pore and the structure of both the pore-forming and auxiliary subunits. Voltage-gated calcium channels are subject to multiple pathways of modulation by G-protein and second messenger regulation. Furthermore, their trafficking pathways, subcellular localisation and functional specificity are the subjects of active investigation.
12
Kramer, Gerhard. "Information Rates for Channels with Fading, Side Information and Adaptive Codewords". Entropy 25, n. 5 (27 aprile 2023): 728. http://dx.doi.org/10.3390/e25050728.
Abstract (sommario):
Generalized mutual information (GMI) is used to compute achievable rates for fading channels with various types of channel state information at the transmitter (CSIT) and receiver (CSIR). The GMI is based on variations of auxiliary channel models with additive white Gaussian noise (AWGN) and circularly-symmetric complex Gaussian inputs. One variation uses reverse channel models with minimum mean square error (MMSE) estimates that give the largest rates but are challenging to optimize. A second variation uses forward channel models with linear MMSE estimates that are easier to optimize. Both model classes are applied to channels where the receiver is unaware of the CSIT and for which adaptive codewords achieve capacity. The forward model inputs are chosen as linear functions of the adaptive codeword’s entries to simplify the analysis. For scalar channels, the maximum GMI is then achieved by a conventional codebook, where the amplitude and phase of each channel symbol are modified based on the CSIT. The GMI increases by partitioning the channel output alphabet and using a different auxiliary model for each partition subset. The partitioning also helps to determine the capacity scaling at high and low signal-to-noise ratios. A class of power control policies is described for partial CSIR, including a MMSE policy for full CSIT. Several examples of fading channels with AWGN illustrate the theory, focusing on on-off fading and Rayleigh fading. The capacity results generalize to block fading channels with in-block feedback, including capacity expressions in terms of mutual and directed information.
13
Tian, Yutao, Florian Ullrich, Rong Xu, Stefan H. Heinemann, Shangwei Hou e Toshinori Hoshi. "Two distinct effects of PIP2 underlie auxiliary subunit-dependent modulation of Slo1 BK channels". Journal of General Physiology 145, n. 4 (30 marzo 2015): 331–43. http://dx.doi.org/10.1085/jgp.201511363.
Abstract (sommario):
Phosphatidylinositol 4,5-bisphosphate (PIP2) plays a critical role in modulating the function of numerous ion channels, including large-conductance Ca2+- and voltage-dependent K+ (BK, Slo1) channels. Slo1 BK channel complexes include four pore-forming Slo1 (α) subunits as well as various regulatory auxiliary subunits (β and γ) that are expressed in different tissues. We examined the molecular and biophysical mechanisms underlying the effects of brain-derived PIP2 on human Slo1 BK channel complexes with different subunit compositions that were heterologously expressed in human embryonic kidney cells. PIP2 inhibited macroscopic currents through Slo1 channels without auxiliary subunits and through Slo1 + γ1 complexes. In contrast, PIP2 markedly increased macroscopic currents through Slo1 + β1 and Slo1 + β4 channel complexes and failed to alter macroscopic currents through Slo1 + β2 and Slo1 + β2 Δ2–19 channel complexes. Results obtained at various membrane potentials and divalent cation concentrations suggest that PIP2 promotes opening of the ion conduction gate in all channel types, regardless of the specific subunit composition. However, in the absence of β subunits positioned near the voltage-sensor domains (VSDs), as in Slo1 and probably Slo1 + γ1, PIP2 augments the negative surface charge on the cytoplasmic side of the membrane, thereby shifting the voltage dependence of VSD-mediated activation in the positive direction. When β1 or β4 subunits occupy the space surrounding the VSDs, only the stimulatory effect of PIP2 is evident. The subunit compositions of native Slo1 BK channels differ in various cell types; thus, PIP2 may exert distinct tissue- and divalent cation–dependent modulatory influences.
14
Xu, Jia, e Min Li. "Auxiliary Subunits of Shaker-type Potassium Channels". Trends in Cardiovascular Medicine 8, n. 5 (luglio 1998): 229–34. http://dx.doi.org/10.1016/s1050-1738(98)00011-5.
15
Isom, L. "Auxiliary subunits of voltage-gated ion channels". Neuron 12, n. 6 (giugno 1994): 1183–94. http://dx.doi.org/10.1016/0896-6273(94)90436-7.
16
Gandini, María A., Alejandro Sandoval, Ricardo González-Ramírez, Yasuo Mori, Michel de Waard e Ricardo Felix. "Functional Coupling of Rab3-interacting Molecule 1 (RIM1) and L-type Ca2+ Channels in Insulin Release". Journal of Biological Chemistry 286, n. 18 (14 marzo 2011): 15757–65. http://dx.doi.org/10.1074/jbc.m110.187757.
Abstract (sommario):
Insulin release by pancreatic β-cells is regulated by diverse intracellular signals, including changes in Ca2+ concentration resulting from Ca2+ entry through voltage-gated (CaV) channels. It has been reported that the Rab3 effector RIM1 acts as a functional link between neuronal CaV channels and the machinery for exocytosis. Here, we investigated whether RIM1 regulates recombinant and native L-type CaV channels (that play a key role in hormone secretion) and whether this regulation affects insulin release. Whole-cell patch clamp currents were recorded from HEK-293 and insulinoma RIN-m5F cells. RIM1 and CaV channel expression was identified by RT-PCR and Western blot. RIM1-CaV channel interaction was determined by co-immunoprecipitation. Knockdown of RIM1 and CaV channel subunit expression were performed using small interference RNAs. Insulin release was assessed by ELISA. Co-expression of CaV1.2 and CaV1.3 L-type channels with RIM1 in HEK-293 cells revealed that RIM1 may not determine the availability of L-type CaV channels but decreases the rate of inactivation of the whole cell currents. Co-immunoprecipitation experiments showed association of the CaVβ auxiliary subunit with RIM1. The lack of CaVβ expression suppressed channel regulation by RIM1. Similar to the heterologous system, an increase of current inactivation was observed upon knockdown of endogenous RIM1. Co-immunoprecipitation showed association of CaVβ and RIM1 in insulin-secreting RIN-m5F cells. Knockdown of RIM1 notably impaired high K+-stimulated insulin secretion in the RIN-m5F cells. These data unveil a novel functional coupling between RIM1 and the L-type CaV channels via the CaVβ auxiliary subunit that contribute to determine insulin secretion.
17
Malloy, Cole, Maisie Ahern, Lin Lin e Dax A. Hoffman. "Neuronal Roles of the Multifunctional Protein Dipeptidyl Peptidase-like 6 (DPP6)". International Journal of Molecular Sciences 23, n. 16 (16 agosto 2022): 9184. http://dx.doi.org/10.3390/ijms23169184.
Abstract (sommario):
The concerted action of voltage-gated ion channels in the brain is fundamental in controlling neuronal physiology and circuit function. Ion channels often associate in multi-protein complexes together with auxiliary subunits, which can strongly influence channel expression and function and, therefore, neuronal computation. One such auxiliary subunit that displays prominent expression in multiple brain regions is the Dipeptidyl aminopeptidase-like protein 6 (DPP6). This protein associates with A-type K+ channels to control their cellular distribution and gating properties. Intriguingly, DPP6 has been found to be multifunctional with an additional, independent role in synapse formation and maintenance. Here, we feature the role of DPP6 in regulating neuronal function in the context of its modulation of A-type K+ channels as well as its independent involvement in synaptic development. The prevalence of DPP6 in these processes underscores its importance in brain function, and recent work has identified that its dysfunction is associated with host of neurological disorders. We provide a brief overview of these and discuss research directions currently underway to advance our understanding of the contribution of DPP6 to their etiology.
18
Li, Qin, Xin Guan, Karen Yen, Jiyuan Zhang e Jiusheng Yan. "The single transmembrane segment determines the modulatory function of the BK channel auxiliary γ subunit". Journal of General Physiology 147, n. 4 (28 marzo 2016): 337–51. http://dx.doi.org/10.1085/jgp.201511551.
Abstract (sommario):
The large-conductance, calcium-activated potassium (BK) channels consist of the pore-forming, voltage- and Ca2+-sensing α subunits (BKα) and the tissue-specific auxiliary β and γ subunits. The BK channel γ1 subunit is a leucine-rich repeat (LRR)–containing membrane protein that potently facilitates BK channel activation in many tissues and cell types through a vast shift in the voltage dependence of channel activation by ∼140 mV in the hyperpolarizing direction. In this study, we found that the single transmembrane (TM) segment together with its flanking charged residues is sufficient to fully modulate BK channels upon its transplantation into the structurally unrelated β1 subunit. We identified Phe273 and its neighboring residues in the middle of the TM segment and a minimum of three intracellular juxtamembrane Arg residues as important for the γ1 subunit’s modulatory function and observed functional coupling between residues of these two locations. We concluded that the TM segment is a key molecular determinant for channel association and modulation and that the intracellular positively charged cluster is involved mainly in channel association, likely through its TM-anchoring effect. Our findings provide insights into the structure–function relationship of the γ1 subunit in understanding its potent modulatory effects on BK channels.
19
Tong, Mingjie, e R. Keith Duncan. "Tamoxifen inhibits BK channels in chick cochlea without alterations in voltage-dependent activation". American Journal of Physiology-Cell Physiology 297, n. 1 (luglio 2009): C75—C85. http://dx.doi.org/10.1152/ajpcell.00659.2008.
Abstract (sommario):
Large-conductance, Ca2+-activated, and voltage-gated potassium channels (BK, BKCa, or Maxi-K) play an important role in electrical tuning in nonmammalian vertebrate hair cells. Systematic changes in tuning frequency along the tonotopic axis largely result from variations in BK channel kinetics, but the molecular changes underpinning these functional variations remain unknown. Auxiliary β1 have been implicated in low-frequency tuning at the cochlear apex because these subunits dramatically slow channel kinetics. Tamoxifen (Tx), a (xeno)estrogen compound known to activate BK channels through the β-subunit, was used to test for the functional presence of β1. The hypotheses were that Tx would activate the majority of BK channels in hair cells from the cochlear apex due to the presence of β1 and that the level of activation would exhibit a tonotopic gradient following the expression profile of β1. Outside-out patches of BK channels were excised from tall hair cells along the apical half of the chicken basilar papilla. In low-density patches, single-channel conductance was reduced and the averaged open probability was unaffected by Tx. In high-density patches, the amplitude of ensemble-averaged BK current was inhibited, whereas half-activation potential and activation kinetics were unaffected by Tx. In both cases, no tonotopic Tx-dependent activation of channel activity was observed. Therefore, contrary to the hypotheses, electrophysiological assessment suggests that molecular mechanisms other than auxiliary β-subunits are involved in generating a tonotopic distribution of BK channel kinetics and electric tuning in chick basilar papilla.
20
Vacher, Hélène, Jae-Won Yang, Oscar Cerda, Amapola Autillo-Touati, Bénédicte Dargent e James S. Trimmer. "Cdk-mediated phosphorylation of the Kvβ2 auxiliary subunit regulates Kv1 channel axonal targeting". Journal of Cell Biology 192, n. 5 (28 febbraio 2011): 813–24. http://dx.doi.org/10.1083/jcb.201007113.
Abstract (sommario):
Kv1 channels are concentrated at specific sites in the axonal membrane, where they regulate neuronal excitability. Establishing these distributions requires regulated dissociation of Kv1 channels from the neuronal trafficking machinery and their subsequent insertion into the axonal membrane. We find that the auxiliary Kvβ2 subunit of Kv1 channels purified from brain is phosphorylated on serine residues 9 and 31, and that cyclin-dependent kinase (Cdk)–mediated phosphorylation at these sites negatively regulates the interaction of Kvβ2 with the microtubule plus end–tracking protein EB1. Endogenous Cdks, EB1, and Kvβ2 phosphorylated at serine 31 are colocalized in the axons of cultured hippocampal neurons, with enrichment at the axon initial segment (AIS). Acute inhibition of Cdk activity leads to intracellular accumulation of EB1, Kvβ2, and Kv1 channel subunits within the AIS. These studies reveal a new regulatory mechanism for the targeting of Kv1 complexes to the axonal membrane through the reversible Cdk phosphorylation-dependent binding of Kvβ2 to EB1.
21
Gurnett, Christina A., e Kevin P. Campbell. "Transmembrane Auxiliary Subunits of Voltage-dependent Ion Channels". Journal of Biological Chemistry 271, n. 45 (8 novembre 1996): 27975–78. http://dx.doi.org/10.1074/jbc.271.45.27975.
22
Sun, Wenhao, Yuchen He, Tianfeng Yan, Zhongdong Wu e Yide Ma. "Training of Deep Joint Transmitter-Receiver Optimized Communication System without Auxiliary Tools". Electronics 13, n. 5 (21 febbraio 2024): 831. http://dx.doi.org/10.3390/electronics13050831.
Abstract (sommario):
Deep Joint transmitter-receiver optimized communication system (Deep JTROCS) is a new physical layer communication system. It integrates the functions of various signal processing blocks into deep neural networks in the transmitter and receiver. Therefore, Deep JTROCS can approach the optimal state at the system level by the joint training of these neural networks. However, due to the non-differentiable feature of the channel, the back-propagation of Deep JTROCS training gradients is hindered which hinders the training of the neural networks in the transmitter. Although researchers have proposed methods to train transmitters using auxiliary tools such as channel models or feedback links, these tools are not available in many real-world communication scenarios, limiting the application of Deep JTROCS. In this paper, we propose a new method to use undertrained Deep JTROCS to transmit the training signals and use these signals to reconstruct the training gradient of the neural networks in the transmitter, thus avoiding the use of an additional reliable link. The experimental results show that the proposed method outperforms the additional link-based approach in different tasks and channels. In addition, experiments conducted on real wireless channels validate the practical feasibility of the method.
23
Jespersen, Thomas, Morten Grunnet e Søren-Peter Olesen. "The KCNQ1 Potassium Channel: From Gene to Physiological Function". Physiology 20, n. 6 (dicembre 2005): 408–16. http://dx.doi.org/10.1152/physiol.00031.2005.
Abstract (sommario):
The voltage-gated KCNQ1 (KvLQT1, Kv7.1) potassium channel plays a crucial role in shaping the cardiac action potential as well as in controlling the water and salt homeostasis in several epithelial tissues. KCNQ1 channels in these tissues are tightly regulated by auxiliary proteins and accessory factors, capable of modulating the properties of the channel complexes. This paper reviews the current knowledge about the KCNQ1 channel with a major focus on interacting proteins and physiological functions.
24
Mohler, Peter J., e Xander H. T. Wehrens. "Mechanisms of Human Arrhythmia Syndromes: Abnormal Cardiac Macromolecular Interactions". Physiology 22, n. 5 (ottobre 2007): 342–50. http://dx.doi.org/10.1152/physiol.00018.2007.
Abstract (sommario):
Many cardiac ion channels exist within macromolecular signaling complexes, comprised of pore-forming subunits that associate with auxiliary subunits, regulatory enzymes, and targeting proteins. This complex protein assembly ensures proper modulation of channel activity and ion homeostasis. The association of genetic defects in regulatory and targeting proteins to inherited arrhythmia syndromes has led to a better understanding of the critical role these proteins play in ion channel modulation.
25
Peng, Bo, Wenyi Zhang, Yuxin Hu, Qingwei Chu e Qianqian Li. "LRFFNet: Large Receptive Field Feature Fusion Network for Semantic Segmentation of SAR Images in Building Areas". Remote Sensing 14, n. 24 (12 dicembre 2022): 6291. http://dx.doi.org/10.3390/rs14246291.
Abstract (sommario):
There are limited studies on the semantic segmentation of high-resolution synthetic aperture radar (SAR) images in building areas due to speckle noise and geometric distortion. For this challenge, we propose the large receptive field feature fusion network (LRFFNet), which contains a feature extractor, a cascade feature pyramid module (CFP), a large receptive field channel attention module (LFCA), and an auxiliary branch. SAR images only contain single-channel information and have a low signal-to-noise ratio. Using only one level of features extracted by the feature extractor will result in poor segmentation results. Therefore, we design the CFP module; it can integrate different levels of features through multi-path connection. Due to the problem of geometric distortion in SAR images, the structural and semantic information is not obvious. In order to pick out feature channels that are useful for segmentation, we design the LFCA module, which can reassign the weight of channels through the channel attention mechanism with a large receptive field to help the network focus on more effective channels. SAR images do not include color information, and the identification of ground object categories is prone to errors, so we design the auxiliary branch. The branch uses the full convolution structure to optimize training results and reduces the phenomenon of recognizing objects outside the building area as buildings. Compared with state-of-the-art (SOTA) methods, our proposed network achieves higher scores in evaluation indicators and shows excellent competitiveness.
26
Vacher, Helene, Durga P. Mohapatra e James S. Trimmer. "Localization and Targeting of Voltage-Dependent Ion Channels in Mammalian Central Neurons". Physiological Reviews 88, n. 4 (ottobre 2008): 1407–47. http://dx.doi.org/10.1152/physrev.00002.2008.
Abstract (sommario):
The intrinsic electrical properties and the synaptic input-output relationships of neurons are governed by the action of voltage-dependent ion channels. The localization of specific populations of ion channels with distinct functional properties at discrete sites in neurons dramatically impacts excitability and synaptic transmission. Molecular cloning studies have revealed a large family of genes encoding voltage-dependent ion channel principal and auxiliary subunits, most of which are expressed in mammalian central neurons. Much recent effort has focused on determining which of these subunits coassemble into native neuronal channel complexes, and the cellular and subcellular distributions of these complexes, as a crucial step in understanding the contribution of these channels to specific aspects of neuronal function. Here we review progress made on recent studies aimed to determine the cellular and subcellular distribution of specific ion channel subunits in mammalian brain neurons using in situ hybridization and immunohistochemistry. We also discuss the repertoire of ion channel subunits in specific neuronal compartments and implications for neuronal physiology. Finally, we discuss the emerging mechanisms for determining the discrete subcellular distributions observed for many neuronal ion channels.
27
Han, Ye, Kyle Lyman, Matt Clutter, Gary E. Schiltz, Quratul-Ain Ismail, Diego Bleifuss Prados, Chi-Hao Luan e Dane M. Chetkovich. "Identification of Small-Molecule Inhibitors of Hyperpolarization-Activated Cyclic Nucleotide–Gated Channels". Journal of Biomolecular Screening 20, n. 9 (4 giugno 2015): 1124–31. http://dx.doi.org/10.1177/1087057115589590.
Abstract (sommario):
Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels function in the brain to limit neuronal excitability. Limiting the activity of these channels has been proposed as a therapy for major depressive disorder, but the critical role of HCN channels in cardiac pacemaking has limited efforts to develop therapies directed at the channel. Previous studies indicated that the function of HCN is tightly regulated by its auxiliary subunit, tetratricopeptide repeat–containing Rab8b interacting protein (TRIP8b), which is not expressed in the heart. To target the function of the HCN channel in the brain without affecting the channel’s function in the heart, we propose disrupting the interaction between HCN and TRIP8b. We developed a high-throughput fluorescence polarization (FP) assay to identify small molecules capable of disrupting this interaction. We used this FP assay to screen a 20,000-compound library and identified a number of active compounds. The active compounds were validated using an orthogonal AlphaScreen assay to identify one compound (0.005%) as the first confirmed hit for inhibiting the HCN-TRIP8b interaction. Identifying small molecules capable of disrupting the interaction between HCN and TRIP8b should enable the development of new research tools and small-molecule therapies that could benefit patients with depression.
28
Ancatén-González, Carlos, Ignacio Segura, Rosangelina Alvarado-Sánchez, Andrés E. Chávez e Ramon Latorre. "Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions". International Journal of Molecular Sciences 24, n. 4 (8 febbraio 2023): 3407. http://dx.doi.org/10.3390/ijms24043407.
Abstract (sommario):
BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca2+ sensitivity, voltage dependence and gating properties. BK channels are abundantly expressed throughout the brain and in different compartments within a single neuron, including axons, synaptic terminals, dendritic arbors, and spines. Their activation produces a massive efflux of K+ ions that hyperpolarizes the cellular membrane. Together with their ability to detect changes in intracellular Ca2+ concentration, BK channels control neuronal excitability and synaptic communication through diverse mechanisms. Moreover, increasing evidence indicates that dysfunction of BK channel-mediated effects on neuronal excitability and synaptic function has been implicated in several neurological disorders, including epilepsy, fragile X syndrome, mental retardation, and autism, as well as in motor and cognitive behavior. Here, we discuss current evidence highlighting the physiological importance of this ubiquitous channel in regulating brain function and its role in the pathophysiology of different neurological disorders.
29
Hoshi, T., A. Pantazis e R. Olcese. "Transduction of Voltage and Ca2+ Signals by Slo1 BK Channels". Physiology 28, n. 3 (maggio 2013): 172–89. http://dx.doi.org/10.1152/physiol.00055.2012.
Abstract (sommario):
Large-conductance Ca2+- and voltage-gated K+ channels are activated by an increase in intracellular Ca2+ concentration and/or depolarization. The channel activation mechanism is well described by an allosteric model encompassing the gate, voltage sensors, and Ca2+ sensors, and the model is an excellent framework to understand the influences of auxiliary β and γ subunits and regulatory factors such as Mg2+. Recent advances permit elucidation of structural correlates of the biophysical mechanism.
30
Cohen, Risa M., Jason D. Foell, Ravi C. Balijepalli, Vaibhavi Shah, Johannes W. Hell e 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, n. 5 (maggio 2005): H2363—H2374. http://dx.doi.org/10.1152/ajpheart.00348.2004.
Abstract (sommario):
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.
31
Qin, Ning, Riccardo Olcese, Enrico Stefani e Lutz Birnbaumer. "Modulation of human neuronal α1E-type calcium channel by α2δ-subunit". American Journal of Physiology-Cell Physiology 274, n. 5 (1 maggio 1998): C1324—C1331. http://dx.doi.org/10.1152/ajpcell.1998.274.5.c1324.
Abstract (sommario):
Calcium channels are composed of a pore-forming subunit, α1, and at least two auxiliary subunits, β- and α2δ-subunits. It is well known that β-subunits regulate most of the properties of the channel. The function of α2δ-subunit is less understood. In this study, the effects of the calcium channel α2δ-subunit on the neuronal α1E voltage-gated calcium channel expressed in Xenopus oocytes was investigated without and with simultaneous coexpression of either the β1b- or the β2a-subunit. Most aspects of α1E function were affected by α2δ. Thus α2δ caused a shift in the current-voltage and conductance-voltage curves toward more positive potentials and accelerated activation, deactivation, and the installation of the inactivation process. In addition, the efficiency with which charge movement is coupled to pore opening assessed by determining ratios of limiting conductance to limiting charge movement was decreased by α2δ by factors that ranged from 1.6 ( P < 0.01) for α1E-channels to 3.0 ( P < 0.005) for α1Eβ1b-channels. These results indicate that α2δ facilitates the expression and the maturation of α1E-channels and converts these channels into molecules responding more rapidly to voltage.
32
Dshalalow, Jewgeni. "On a multi-channel transportation loss system with controlled input and controlled service". Journal of Applied Mathematics and Simulation 1, n. 1 (1 gennaio 1987): 41–55. http://dx.doi.org/10.1155/s1048953388000048.
Abstract (sommario):
A multi-channel loss queueing system is investigated. The input stream is a controlled point process. The service in each of m parallel channels depends on the state of the system at certain moments of time when input and service may be controlled. To obtain explicitly the limiting distribution of the main process (Zt) (the number of busy channels) in equilibrium, an auxiliary three dimensional process with two additional components (one of them is a semi-Markov process) is treated as semi-regenerative process. An optimization problem is discussed. Simple expressions for an objective function are derived.
33
Dolphin, Annette C. "Voltage-gated calcium channel α2δ subunits: an assessment of proposed novel roles". F1000Research 7 (21 novembre 2018): 1830. http://dx.doi.org/10.12688/f1000research.16104.1.
Abstract (sommario):
Voltage-gated calcium (CaV) channels are associated with β and α2δ auxiliary subunits. This review will concentrate on the function of the α2δ protein family, which has four members. The canonical role for α2δ subunits is to convey a variety of properties on the CaV1 and CaV2 channels, increasing the density of these channels in the plasma membrane and also enhancing their function. More recently, a diverse spectrum of non-canonical interactions for α2δ proteins has been proposed, some of which involve competition with calcium channels for α2δ or increase α2δ trafficking and others which mediate roles completely unrelated to their calcium channel function. The novel roles for α2δ proteins which will be discussed here include association with low-density lipoprotein receptor-related protein 1 (LRP1), thrombospondins, α-neurexins, prion proteins, large conductance (big) potassium (BK) channels, and N-methyl-d-aspartate (NMDA) receptors.
34
Zhao, Juan, Michael E. O'Leary e Mohamed Chahine. "Regulation of Nav1.6 and Nav1.8 peripheral nerve Na+ channels by auxiliary β-subunits". Journal of Neurophysiology 106, n. 2 (agosto 2011): 608–19. http://dx.doi.org/10.1152/jn.00107.2011.
Abstract (sommario):
Voltage-gated Na+ (Nav) channels are composed of a pore-forming α-subunit and one or more auxiliary β-subunits. The present study investigated the regulation by the β-subunit of two Na+ channels (Nav1.6 and Nav1.8) expressed in dorsal root ganglion (DRG) neurons. Single cell RT-PCR was used to show that Nav1.8, Nav1.6, and β1–β3 subunits were widely expressed in individually harvested small-diameter DRG neurons. Coexpression experiments were used to assess the regulation of Nav1.6 and Nav1.8 by β-subunits. The β1-subunit induced a 2.3-fold increase in Na+ current density and hyperpolarizing shifts in the activation (−4 mV) and steady-state inactivation (−4.7 mV) of heterologously expressed Nav1.8 channels. The β4-subunit caused more pronounced shifts in activation (−16.7 mV) and inactivation (−9.3 mV) but did not alter the current density of cells expressing Nav1.8 channels. The β3-subunit did not alter Nav1.8 gating but significantly reduced the current density by 31%. This contrasted with Nav1.6, where the β-subunits were relatively weak regulators of channel function. One notable exception was the β4-subunit, which induced a hyperpolarizing shift in activation (−7.6 mV) but no change in the inactivation or current density of Nav1.6. The β-subunits differentially regulated the expression and gating of Nav1.8 and Nav1.6. To further investigate the underlying regulatory mechanism, β-subunit chimeras containing portions of the strongly regulating β1-subunit and the weakly regulating β2-subunit were generated. Chimeras retaining the COOH-terminal domain of the β1-subunit produced hyperpolarizing shifts in gating and increased the current density of Nav1.8, similar to that observed for wild-type β1-subunits. The intracellular COOH-terminal domain of the β1-subunit appeared to play an essential role in the regulation of Nav1.8 expression and gating.
35
Cheng, Hao-Chung, e Min-Hsiu Hsieh. "Concavity of the Auxiliary Function for Classical-Quantum Channels". IEEE Transactions on Information Theory 62, n. 10 (ottobre 2016): 5960–65. http://dx.doi.org/10.1109/tit.2016.2598835.
36
Andreozzi, Assunta, Oronzio Manca e Vincenzo Naso. "Natural convection in vertical channels with an auxiliary plate". International Journal of Numerical Methods for Heat & Fluid Flow 12, n. 6 (settembre 2002): 716–34. http://dx.doi.org/10.1108/09615530210438364.
37
Pancaroglu, Raika, e Filip Van Petegem. "Calcium Channelopathies: Structural Insights into Disorders of the Muscle Excitation–Contraction Complex". Annual Review of Genetics 52, n. 1 (23 novembre 2018): 373–96. http://dx.doi.org/10.1146/annurev-genet-120417-031311.
Abstract (sommario):
Ion channels are membrane proteins responsible for the passage of ions down their electrochemical gradients and across biological membranes. In this, they generate and shape action potentials and provide secondary messengers for various signaling pathways. They are often part of larger complexes containing auxiliary subunits and regulatory proteins. Channelopathies arise from mutations in the genes encoding ion channels or their associated proteins. Recent advances in cryo-electron microscopy have resulted in an explosion of ion channel structures in multiple states, generating a wealth of new information on channelopathies. Disease-associated mutations fall into different categories, interfering with ion permeation, protein folding, voltage sensing, ligand and protein binding, and allosteric modulation of channel gating. Prime examples of these are Ca2+-selective channels expressed in myocytes, for which multiple structures in distinct conformational states have recently been uncovered. We discuss the latest insights into these calcium channelopathies from a structural viewpoint.
38
Brown, Patricia M. G. E., Hugo McGuire e Derek Bowie. "Stargazin and cornichon-3 relieve polyamine block of AMPA receptors by enhancing blocker permeation". Journal of General Physiology 150, n. 1 (8 dicembre 2017): 67–82. http://dx.doi.org/10.1085/jgp.201711895.
Abstract (sommario):
Most ligand- and voltage-gated ion channels assemble as signaling complexes consisting of pore-forming and auxiliary subunits. In the mammalian brain, AMPA-type ionotropic glutamate receptors (AMPARs) coassemble with several families of auxiliary subunits that regulate channel gating as well as ion channel block and permeation. Previous work has shown that auxiliary proteins stargazin (or γ2) and cornichon-3 (CNIH-3) attenuate the cytoplasmic polyamine channel block of AMPARs, although the underlying mechanism has yet to be established. Here, we show that γ2 and CNIH-3 relieve channel block by enhancing the rate of blocker permeation. Surprisingly, the relative permeability of the polyamine spermine (Spm) through the pore of the AMPAR-γ2 or -CNIH-3 complexes is considerably more than AMPARs expressed alone. Spm permeability is comparable to that of Na+ for the GluA2-γ2 complex and four times greater than Na+ with GluA2 + CNIH-3. A modified model of permeant channel block fully accounts for both the voltage- and time-dependent nature of Spm block. Estimates of block rate constants reveal that auxiliary subunits do not attenuate block by shifting the location of the block site within the membrane electric field, and they do not affect the blocker’s ability to reach it. Instead, γ2 and CNIH-3 relieve channel block by facilitating the blocker’s exit rates from the open channel. From a physiological perspective, the relief of channel block exerted by γ2 and CNIH-3 ensures that there is unfettered signaling by AMPARs at glutamatergic synapses. Moreover, the pronounced ability of AMPARs to transport polyamines may have an unexpected role in regulating cellular polyamine levels.
39
He, Yanjun, e Jianhua Li. "Stress Distribution and Optimum Spacing Determination of Double-Withdrawal-Channel Surrounding Rocks: A Case Study of Chinese Coal Mine". Shock and Vibration 2021 (3 luglio 2021): 1–16. http://dx.doi.org/10.1155/2021/9973634.
Abstract (sommario):
In this study, the 31113 fully mechanised working face in the Lijiahao Coal Mine was selected as the project background. The failure characteristics and optimum spacing of a double-withdrawal-channel surrounding rock were extensively investigated through field measurements, theoretical analysis, and numerical simulations. The following results were obtained. The loading influence range of the working face was fixed. Under the influence of mining, the stress distribution variation in the double-withdrawal channels with spacing and the influence of stress distribution on the surrounding rock stability of the withdrawal channels were determined. The optimum distance between the double-withdrawal channels to achieve the stability of the surrounding rock was at least 25 m, and engineering measures are required to limit the mining height in the final mining stage. The rationality of the main and auxiliary withdrawal channel spacing of 25 m and measures to limit the mining height in the final stage were demonstrated. The findings of this study provide a valuable reference for constructing the layout of withdrawal channels in the adjacent working faces of the same mining area.
40
Sek, Aleksandra, Rafal P. Kampa, Bogusz Kulawiak, Adam Szewczyk e Piotr Bednarczyk. "Identification of the Large-Conductance Ca2+-Regulated Potassium Channel in Mitochondria of Human Bronchial Epithelial Cells". Molecules 26, n. 11 (27 maggio 2021): 3233. http://dx.doi.org/10.3390/molecules26113233.
Abstract (sommario):
Mitochondria play a key role in energy metabolism within the cell. Potassium channels such as ATP-sensitive, voltage-gated or large-conductance Ca2+-regulated channels have been described in the inner mitochondrial membrane. Several hypotheses have been proposed to describe the important roles of mitochondrial potassium channels in cell survival and death pathways. In the current study, we identified two populations of mitochondrial large-conductance Ca2+-regulated potassium (mitoBKCa) channels in human bronchial epithelial (HBE) cells. The biophysical properties of the channels were characterized using the patch-clamp technique. We observed the activity of the channel with a mean conductance close to 285 pS in symmetric 150/150 mM KCl solution. Channel activity was increased upon application of the potassium channel opener NS11021 in the micromolar concentration range. The channel activity was completely inhibited by 1 µM paxilline and 300 nM iberiotoxin, selective inhibitors of the BKCa channels. Based on calcium and iberiotoxin modulation, we suggest that the C-terminus of the protein is localized to the mitochondrial matrix. Additionally, using RT-PCR, we confirmed the presence of α pore-forming (Slo1) and auxiliary β3-β4 subunits of BKCa channel in HBE cells. Western blot analysis of cellular fractions confirmed the mitochondrial localization of α pore-forming and predominately β3 subunits. Additionally, the regulation of oxygen consumption and membrane potential of human bronchial epithelial mitochondria in the presence of the potassium channel opener NS11021 and inhibitor paxilline were also studied. In summary, for the first time, the electrophysiological and functional properties of the mitoBKCa channel in a bronchial epithelial cell line were described.
41
Bao, Lin, e Daniel H. Cox. "Gating and Ionic Currents Reveal How the BKCa Channel's Ca2+ Sensitivity Is Enhanced by its β1 Subunit". Journal of General Physiology 126, n. 4 (26 settembre 2005): 393–412. http://dx.doi.org/10.1085/jgp.200509346.
Abstract (sommario):
Large-conductance Ca2+-activated K+ channels (BKCa channels) are regulated by the tissue-specific expression of auxiliary β subunits. β1 is predominately expressed in smooth muscle, where it greatly enhances the BKCa channel's Ca2+ sensitivity, an effect that is required for proper regulation of smooth muscle tone. Here, using gating current recordings, macroscopic ionic current recordings, and unitary ionic current recordings at very low open probabilities, we have investigated the mechanism that underlies this effect. Our results may be summarized as follows. The β1 subunit has little or no effect on the equilibrium constant of the conformational change by which the BKCa channel opens, and it does not affect the gating charge on the channel's voltage sensors, but it does stabilize voltage sensor activation, both when the channel is open and when it is closed, such that voltage sensor activation occurs at more negative voltages with β1 present. Furthermore, β1 stabilizes the active voltage sensor more when the channel is closed than when it is open, and this reduces the factor D by which voltage sensor activation promotes opening by ∼24% (16.8→12.8). The effects of β1 on voltage sensing enhance the BKCa channel's Ca2+ sensitivity by decreasing at most voltages the work that Ca2+ binding must do to open the channel. In addition, however, in order to fully account for the increase in efficacy and apparent Ca2+ affinity brought about by β1 at negative voltages, our studies suggest that β1 also decreases the true Ca2+ affinity of the closed channel, increasing its Ca2+ dissociation constant from ∼3.7 μM to between 4.7 and 7.1 μM, depending on how many binding sites are affected.
42
Garcia, M. L., H. G. Knaus, P. Munujos, R. S. Slaughter e G. J. Kaczorowski. "Charybdotoxin and its effects on potassium channels". American Journal of Physiology-Cell Physiology 269, n. 1 (1 luglio 1995): C1—C10. http://dx.doi.org/10.1152/ajpcell.1995.269.1.c1.
Abstract (sommario):
Over the last few years, a considerable amount of information has been obtained regarding K+ channels. Different areas of research have contributed to knowledge in this field. Charybdotoxin (ChTX), a 37-amino acid peptide isolated from venom of the scorpion Leiurus quinquestriatus var. hebraeus, represents a remarkable tool for studying K+ channels. With its use, it has been possible to purify the high-conductance Ca(2+)-activated K+ (maxi-K) channel to homogeneity and determine the subunit composition of this channel. This has led to the discovery of an auxiliary beta-subunit that, when coexpressed with the pore-forming subunit, mSlo, alters the biophysical and pharmacological properties of this latter subunit. With the feasibility of producing large amounts of ChTX by recombinant techniques and the knowledge of the three-dimensional structure of the peptide, it has been possible to carry out site-directed mutagenesis studies and obtain a picture of the interaction surface of the toxin with two channels, maxi-K and Shaker, and to derive a picture of the complementary surface of the receptor in these two channels. Finally, ChTX, and the more selective K+ channel toxins that were subsequently discovered, have provided us with unique tools not only to determine the functional role that K+ channels play in target tissues but also to develop the molecular pharmacology of these channels.
43
Brager, Darrin H., Alan S. Lewis, Dane M. Chetkovich e Daniel Johnston. "Short- and long-term plasticity in CA1 neurons from mice lacking h-channel auxiliary subunit TRIP8b". Journal of Neurophysiology 110, n. 10 (15 novembre 2013): 2350–57. http://dx.doi.org/10.1152/jn.00218.2013.
Abstract (sommario):
Hyperpolarization-activated cyclic nucleotide-gated nonselective cation channels (HCN or h-channels) are important regulators of neuronal physiology contributing to passive membrane properties, such as resting membrane potential and input resistance ( RN), and to intrinsic oscillatory activity and synaptic integration. The correct membrane targeting of h-channels is regulated in part by the auxiliary h-channel protein TRIP8b. The genetic deletion of TRIP8b results in a loss of functional h-channels, which affects the postsynaptic integrative properties of neurons. We investigated the impact of TRIP8b deletion on long-term potentiation (LTP) at the two major excitatory inputs to CA1 pyramidal neurons: Schaffer collateral (SC) and perforant path (PP). We found that SC LTP was not significantly different between neurons from wild-type and TRIP8b-knockout mice. There was, however, significantly more short-term potentiation in knockout neurons. We also found that the persistent increase in h-current ( Ih) that normally occurs after LTP induction was absent in knockout neurons. The lack of Ih plasticity was not restricted to activity-dependent induction, because the depletion of intracellular calcium stores also failed to produce the expected increase in Ih. Interestingly, pairing of SC and PP inputs resulted in a form of LTP in knockout neurons that did not occur in wild-type neurons. These results suggest that the physiological impact of TRIP8b deletion is not restricted to the integrative properties of neurons but also includes both synaptic and intrinsic plasticity.
44
Zuo, Hao, Ian Glaaser, Yulin Zhao, Igor Kurinov, Lidia Mosyak, Haonan Wang, Jonathan Liu et al. "Structural basis for auxiliary subunit KCTD16 regulation of the GABABreceptor". Proceedings of the National Academy of Sciences 116, n. 17 (10 aprile 2019): 8370–79. http://dx.doi.org/10.1073/pnas.1903024116.
Abstract (sommario):
Metabotropic GABABreceptors mediate a significant fraction of inhibitory neurotransmission in the brain. Native GABABreceptor complexes contain the principal subunits GABAB1and GABAB2, which form an obligate heterodimer, and auxiliary subunits, known as potassium channel tetramerization domain-containing proteins (KCTDs). KCTDs interact with GABABreceptors and modify the kinetics of GABABreceptor signaling. Little is known about the molecular mechanism governing the direct association and functional coupling of GABABreceptors with these auxiliary proteins. Here, we describe the high-resolution structure of the KCTD16 oligomerization domain in complex with part of the GABAB2receptor. A single GABAB2C-terminal peptide is bound to the interior of an open pentamer formed by the oligomerization domain of five KCTD16 subunits. Mutation of specific amino acids identified in the structure of the GABAB2–KCTD16 interface disrupted both the biochemical association and functional modulation of GABABreceptors and G protein-activated inwardly rectifying K+channel (GIRK) channels. These interfacial residues are conserved among KCTDs, suggesting a common mode of KCTD interaction with GABABreceptors. Defining the binding interface of GABABreceptor and KCTD reveals a potential regulatory site for modulating GABAB-receptor function in the brain.
45
Guntur, Divya, Horst Olschewski, Péter Enyedi, Réka Csáki, Andrea Olschewski e Chandran Nagaraj. "Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation". Biomolecules 11, n. 11 (3 novembre 2021): 1629. http://dx.doi.org/10.3390/biom11111629.
Abstract (sommario):
Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options.
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Maqoud, Fatima, Michela Cetrone, Antonietta Mele e Domenico Tricarico. "Molecular structure and function of big calcium-activated potassium channels in skeletal muscle: pharmacological perspectives". Physiological Genomics 49, n. 6 (1 giugno 2017): 306–17. http://dx.doi.org/10.1152/physiolgenomics.00121.2016.
Abstract (sommario):
The large-conductance Ca2+-activated K+ (BK) channel is broadly expressed in various mammalian cells and tissues such as neurons, skeletal muscles (sarco-BK), and smooth muscles. These channels are activated by changes in membrane electrical potential and by increases in the concentration of intracellular calcium ion (Ca2+). The BK channel is subjected to many mechanisms that add diversity to the BK channel α-subunit gene. These channels are indeed subject to alternative splicing, auxiliary subunits modulation, posttranslational modifications, and protein-protein interactions. BK channels can be modulated by diverse molecules that may induce either an increase or decrease in channel activity. The linkage of these channels to many intracellular metabolites and pathways, as well as their modulation by extracellular natural agents, have been found to be relevant in many physiological processes. BK channel diversity is obtained by means of alternative splicing and modulatory β- and γ-subunits. The association of the α-subunit with β- or with γ-subunits can change the BK channel phenotype, functional diversity, and pharmacological properties in different tissues. In the case of the skeletal muscle BK channel (sarco-BK channel), we established that the main mechanism regulating BK channel diversity is the alternative splicing of the KCNMA1/slo1 gene encoding for the α-subunit generating different splicing isoform in the muscle phenotypes. This finding helps to design molecules selectively targeting the skeletal muscle subtypes. The use of drugs selectively targeting the skeletal muscle BK channels is a promising strategy in the treatment of familial disorders affecting muscular skeletal apparatus including hyperkalemia and hypokalemia periodic paralysis.
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Chen, Zijing, e Craig Montell. "A Family of Auxiliary Subunits of the TRP Cation Channel Encoded by the Complex inaF Locus". Genetics 215, n. 3 (20 maggio 2020): 713–28. http://dx.doi.org/10.1534/genetics.120.303268.
Abstract (sommario):
TRP channels function in many types of sensory receptor cells. Despite extensive analyses, an open question is whether there exists a family of auxiliary subunits, which could influence localization, trafficking, and function of TRP channels. Here, using Drosophila melanogaster, we reveal a previously unknown TRP interacting protein, INAF-C, which is expressed exclusively in the ultraviolet-sensing R7 photoreceptor cells. INAF-C is encoded by an unusual locus comprised of four distinct coding regions, which give rise to four unique single-transmembrane-containing proteins. With the exception of INAF-B, roles for the other INAF proteins were unknown. We found that both INAF-B and INAF-C are required for TRP stability and localization in R7 cells. Conversely, loss of just INAF-B greatly reduced TRP from other types of photoreceptor cells, but not R7. The requirements for TRP and INAF are reciprocal, since loss of TRP decreased the concentrations of both INAF-B and INAF-C. INAF-A, which is not normally expressed in photoreceptor cells, can functionally substitute for INAF-B, indicating that it is a third TRP auxiliary protein. Reminiscent of the structural requirements between Kv channels and KCNE auxiliary subunits, the codependencies of TRP and INAF depended on several transmembrane domains (TMDs) in TRP, and the TMD and the C-terminus of INAF-B. Our studies support a model in which the inaF locus encodes a family of at least three TRP auxiliary subunits.
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Hu, Lei, Bina Santoro, Andrea Saponaro, Haiying Liu, Anna Moroni e Steven Siegelbaum. "Binding of the auxiliary subunit TRIP8b to HCN channels shifts the mode of action of cAMP". Journal of General Physiology 142, n. 6 (25 novembre 2013): 599–612. http://dx.doi.org/10.1085/jgp.201311013.
Abstract (sommario):
Hyperpolarization-activated cyclic nucleotide–regulated cation (HCN) channels generate the hyperpolarization-activated cation current Ih present in many neurons. These channels are directly regulated by the binding of cAMP, which both shifts the voltage dependence of HCN channel opening to more positive potentials and increases maximal Ih at extreme negative voltages where voltage gating is complete. Here we report that the HCN channel brain-specific auxiliary subunit TRIP8b produces opposing actions on these two effects of cAMP. In the first action, TRIP8b inhibits the effect of cAMP to shift voltage gating, decreasing both the sensitivity of the channel to cAMP (K1/2) and the efficacy of cAMP (maximal voltage shift); conversely, cAMP binding inhibits these actions of TRIP8b. These mutually antagonistic actions are well described by a cyclic allosteric mechanism in which TRIP8b binding reduces the affinity of the channel for cAMP, with the affinity of the open state for cAMP being reduced to a greater extent than the cAMP affinity of the closed state. In a second apparently independent action, TRIP8b enhances the action of cAMP to increase maximal Ih. This latter effect cannot be explained by the cyclic allosteric model but results from a previously uncharacterized action of TRIP8b to reduce maximal current through the channel in the absence of cAMP. Because the binding of cAMP also antagonizes this second effect of TRIP8b, application of cAMP produces a larger increase in maximal Ih in the presence of TRIP8b than in its absence. These findings may provide a mechanistic explanation for the wide variability in the effects of modulatory transmitters on the voltage gating and maximal amplitude of Ih reported for different neurons in the brain.
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Zeng, Xu-Hui, J. P. Ding, Xiao-Ming Xia e Christopher J. Lingle. "Gating Properties Conferred on Bk Channels by the β3b Auxiliary Subunit in the Absence of Its Nh2- and Cooh Termini". Journal of General Physiology 117, n. 6 (29 maggio 2001): 607–28. http://dx.doi.org/10.1085/jgp.117.6.607.
Abstract (sommario):
Both β1 and β2 auxiliary subunits of the BK-type K+ channel family profoundly regulate the apparent Ca2+ sensitivity of BK-type Ca2+-activated K+ channels. Each produces a pronounced leftward shift in the voltage of half-activation (V0.5) at a given Ca2+ concentration, particularly at Ca2+ above 1 μM. In contrast, the rapidly inactivating β3b auxiliary produces a leftward shift in activation at Ca2+ below 1 μM. In the companion work (Lingle, C.J., X.-H. Zeng, J.-P. Ding, and X.-M. Xia. 2001. J. Gen. Physiol. 117:583–605, this issue), we have shown that some of the apparent β3b-mediated shift in activation at low Ca2+ arises from rapid unblocking of inactivated channels, unlike the actions of the β1 and β2 subunits. Here, we compare effects of the β3b subunit that arise from inactivation, per se, versus those that may arise from other functional effects of the subunit. In particular, we examine gating properties of the β3b subunit and compare it to β3b constructs lacking either the NH2- or COOH terminus or both. The results demonstrate that, although the NH2 terminus appears to be the primary determinant of the β3b-mediated shift in V0.5 at low Ca2+, removal of the NH2 terminus reveals two other interesting aspects of the action of the β3b subunit. First, the conductance-voltage curves for activation of channels containing the β3b subunit are best described by a double Boltzmann shape, which is proposed to arise from two independent voltage-dependent activation steps. Second, the presence of the β3b subunit results in channels that exhibit an anomalous instantaneous outward current rectification that is correlated with a voltage dependence in the time-averaged single-channel current. The two effects appear to be unrelated, but indicative of the variety of ways that interactions between β and α subunits can affect BK channel function. The COOH terminus of the β3b subunit produces no discernible functional effects.
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Suzuki, Takahiro, e Koichi Takimoto. "Differential expression of Kv4 pore-forming and KChIP auxiliary subunits in rat uterus during pregnancy". American Journal of Physiology-Endocrinology and Metabolism 288, n. 2 (febbraio 2005): E335—E341. http://dx.doi.org/10.1152/ajpendo.00250.2004.
Abstract (sommario):
Regulation of voltage-gated K+ (Kv) channel expression may be involved in controlling contractility of uterine smooth muscle cells during pregnancy. Functional expression of these channels is not only controlled by the levels of pore-forming subunits, but requires their association with auxiliary subunits. Specifically, rapidly inactivating Kv current is prominent in myometrial cells and may be carried by complexes consisting of Kv4 pore-forming and KChIP auxiliary subunits. To determine the molecular identity of the channel complexes and their changes during pregnancy, we examined the expression and localization of these subunits in rat uterus. RT-PCR analysis revealed that rat uterus expressed all three Kv4 pore-forming subunits and KChIP2 and -4 auxiliary subunits. The expression of mRNAs for these subunits was dynamically and region selectively regulated during pregnancy. In the corpus, Kv4.2 mRNA level increased before parturition, whereas the expression of Kv4.1 and Kv4.3 mRNAs decreased during pregnancy. A marked increase in KChIP2 mRNA level was also seen at late gestation. In the cervix, the expression of all three pore-forming and two auxiliary subunit mRNAs increased at late gestation. Immunoprecipitaton followed by immunoblot analysis indicated that Kv4.2-KChIP2 complexes were significant in uterus at late pregnancy. Kv4.2- and KChIP2-immunoreactive proteins were present in both circular and longitudinal myometrial cells. Finally, Kv4.2 and KChIP2 mRNA levels were similarly elevated in pregnant and nonpregnant corpora of one side-conceived rats. These results suggest that diffusible factors coordinate the pregnancy-associated changes in molecular compositions of myometrial Kv4-KChIP channel complexes.