Journal articles: 'Kca1.1'

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Takai, Jun, Alexandra Santu, Haifeng Zheng, Sang Don Koh, Masanori Ohta, Linda M. Filimban, Vincent Lemaître, Ryutaro Teraoka, Hanjoong Jo, and Hiroto Miura. "Laminar shear stress upregulates endothelial Ca2+-activated K+ channels KCa2.3 and KCa3.1 via a Ca2+/calmodulin-dependent protein kinase kinase/Akt/p300 cascade." American Journal of Physiology-Heart and Circulatory Physiology 305, no. 4 (August 15, 2013): H484—H493. http://dx.doi.org/10.1152/ajpheart.00642.2012.

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In endothelial cells (ECs), Ca2+-activated K+ channels KCa2.3 and KCa3.1 play a crucial role in the regulation of arterial tone via producing NO and endothelium-derived hyperpolarizing factors. Since a rise in intracellular Ca2+ levels and activation of p300 histone acetyltransferase are early EC responses to laminar shear stress (LS) for the transcriptional activation of genes, we examined the role of Ca2+/calmodulin-dependent kinase kinase (CaMKK), the most upstream element of a Ca2+/calmodulin-kinase cascade, and p300 in LS-dependent regulation of KCa2.3 and KCa3.1 in ECs. Exposure to LS (15 dyn/cm2) for 24 h markedly increased KCa2.3 and KCa3.1 mRNA expression in cultured human coronary artery ECs (3.2 ± 0.4 and 45 ± 10 fold increase, respectively; P < 0.05 vs. static condition; n = 8–30), whereas oscillatory shear (OS; ± 5 dyn/cm2 × 1 Hz) moderately increased KCa3.1 but did not affect KCa2.3. Expression of KCa2.1 and KCa2.2 was suppressed under both LS and OS conditions, whereas KCa1.1 was slightly elevated in LS and unchanged in OS. Inhibition of CaMKK attenuated LS-induced increases in the expression and channel activity of KCa2.3 and KCa3.1, and in phosphorylation of Akt (Ser473) and p300 (Ser1834). Inhibition of Akt abolished the upregulation of these channels by diminishing p300 phosphorylation. Consistently, disruption of the interaction of p300 with transcription factors eliminated the induction of these channels. Thus a CaMKK/Akt/p300 cascade plays an important role in LS-dependent induction of KCa2.3 and KCa3.1 expression, thereby regulating EC function and adaptation to hemodynamic changes.

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Zhang, Jin, Susan T. Halm, and Dan R. Halm. "Role of the BK channel (KCa1.1) during activation of electrogenic K+ secretion in guinea pig distal colon." American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no. 12 (December 15, 2012): G1322—G1334. http://dx.doi.org/10.1152/ajpgi.00325.2012.

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Secretagogues acting at a variety of receptor types activate electrogenic K+ secretion in guinea pig distal colon, often accompanied by Cl− secretion. Distinct blockers of KCa1.1 (BK, Kcnma1), iberiotoxin (IbTx), and paxilline inhibited the negative short-circuit current ( Isc) associated with K+ secretion. Mucosal addition of IbTx inhibited epinephrine-activated Isc (epi Isc) and transepithelial conductance (epi Gt) consistent with K+ secretion occurring via apical membrane KCa1.1. The concentration dependence of IbTx inhibition of epi Isc yielded an IC50 of 193 nM, with a maximal inhibition of 51%. Similarly, IbTx inhibited epi Gt with an IC50 of 220 nM and maximal inhibition of 48%. Mucosally added paxilline (10 μM) inhibited epi Isc and epi Gt by ∼50%. IbTx and paxilline also inhibited Isc activated by mucosal ATP, supporting apical KCa1.1 as a requirement for this K+ secretagogue. Responses to IbTx and paxilline indicated that a component of K+ secretion occurred during activation of Cl− secretion by prostaglandin-E2 and cholinergic stimulation. Analysis of KCa1.1α mRNA expression in distal colonic epithelial cells indicated the presence of the ZERO splice variant and three splice variants for the COOH terminus. The presence of the regulatory β-subunits KCaβ1 and KCaβ4 also was demonstrated. Immunolocalization supported the presence of KCa1.1α in apical and basolateral membranes of surface and crypt cells. Together these results support a cellular mechanism for electrogenic K+ secretion involving apical membrane KCa1.1 during activation by several secretagogue types, but the observed K+ secretion likely required the activity of additional K+ channel types in the apical membrane.

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Srivastava, Shekhar, Papiya Choudhury, Zhai Li, GongXin Liu, Vivek Nadkarni, Kyung Ko, William A. Coetzee, and Edward Y. Skolnik. "Phosphatidylinositol 3-Phosphate Indirectly Activates KCa3.1 via 14 Amino Acids in the Carboxy Terminus of KCa3.1." Molecular Biology of the Cell 17, no. 1 (January 2006): 146–54. http://dx.doi.org/10.1091/mbc.e05-08-0763.

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KCa3.1 is an intermediate conductance Ca2+-activated K+ channel that is expressed predominantly in hematopoietic cells, smooth muscle cells, and epithelia where it functions to regulate membrane potential, Ca2+ influx, cell volume, and chloride secretion. We recently found that the KCa3.1 channel also specifically requires phosphatidylinositol-3 phosphate [PI(3)P] for channel activity and is inhibited by myotubularin-related protein 6 (MTMR6), a PI(3)P phosphatase. We now show that PI(3)P indirectly activates KCa3.1. Unlike KCa3.1 channels, the related KCa2.1, KCa2.2, or KCa2.3 channels do not require PI(3)P for activity, suggesting that the KCa3.1 channel has evolved a unique means of regulation that is critical for its biological function. By making chimeric channels between KCa3.1 and KCa2.3, we identified a stretch of 14 amino acids in the carboxy-terminal calmodulin binding domain of KCa3.1 that is sufficient to confer regulation of KCa2.3 by PI(3)P. However, mutation of a single potential phosphorylation site in these 14 amino acids did not affect channel activity. These data together suggest that PI(3)P and these 14 amino acids regulate KCa3.1 channel activity by recruiting an as yet to be defined regulatory subunit that is required for Ca2+ gating of KCa3.1.

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Nakamoto, Tetsuji, Victor G. Romanenko, Atsushi Takahashi, Ted Begenisich, and James E. Melvin. "Apical maxi-K (KCa1.1) channels mediate K+ secretion by the mouse submandibular exocrine gland." American Journal of Physiology-Cell Physiology 294, no. 3 (March 2008): C810—C819. http://dx.doi.org/10.1152/ajpcell.00511.2007.

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The exocrine salivary glands of mammals secrete K+ by an unknown pathway that has been associated with HCO3− efflux. However, the present studies found that K+ secretion in the mouse submandibular gland did not require HCO3−, demonstrating that neither K+/HCO3− cotransport nor K+/H+ exchange mechanisms were involved. Because HCO3− did not appear to participate in this process, we tested whether a K channel is required. Indeed, K+ secretion was inhibited >75% in mice with a null mutation in the maxi-K, Ca2+-activated K channel (KCa1.1) but was unchanged in mice lacking the intermediate-conductance IKCa1 channel (KCa3.1). Moreover, paxilline, a specific maxi-K channel blocker, dramatically reduced the K+ concentration in submandibular saliva. The K+ concentration of saliva is well known to be flow rate dependent, the K+ concentration increasing as the flow decreases. The flow rate dependence of K+ secretion was nearly eliminated in K Ca 1.1 null mice, suggesting an important role for KCa1.1 channels in this process as well. Importantly, a maxi-K-like current had not been previously detected in duct cells, the theoretical site of K+ secretion, but we found that KCa1.1 channels localized to the apical membranes of both striated and excretory duct cells, but not granular duct cells, using immunohistochemistry. Consistent with this latter observation, maxi-K currents were not detected in granular duct cells. Taken together, these results demonstrate that the secretion of K+ requires and is likely mediated by KCa1.1 potassium channels localized to the apical membranes of striated and excretory duct cells in the mouse submandibular exocrine gland.

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Stoneking, Colin J., Oshini Shivakumar, David Nicholson Thomas, William H. Colledge, and Michael J. Mason. "Voltage dependence of the Ca2+-activated K+channel KCa3.1 in human erythroleukemia cells." American Journal of Physiology-Cell Physiology 304, no. 9 (May 1, 2013): C858—C872. http://dx.doi.org/10.1152/ajpcell.00368.2012.

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We have isolated a K+-selective, Ca2+-dependent whole cell current and single-channel correlate in the human erythroleukemia (HEL) cell line. The whole cell current was inhibited by the intermediate-conductance KCa3.1 inhibitors clotrimazole, TRAM-34, and charybdotoxin, unaffected by the small-conductance KCa2 family inhibitor apamin and the large-conductance KCa1.1 inhibitors paxilline and iberiotoxin, and augmented by NS309. The single-channel correlate of the whole cell current was blocked by TRAM-34 and clotrimazole, insensitive to paxilline, and augmented by NS309 and had a single-channel conductance in physiological K+gradients of ∼9 pS. RT-PCR revealed that the KCa3.1 gene, but not the KCa1.1 gene, was expressed in HEL cells. The KCa3.1 current, isolated in HEL cells under whole cell patch-clamp conditions, displayed an activated current component during depolarizing voltage steps from hyperpolarized holding potentials and tail currents upon repolarization, consistent with voltage-dependent modulation. This activated current increased with increasing voltage steps above −40 mV and was sensitive to inhibition by clotrimazole, TRAM-34, and charybdotoxin and insensitive to apamin, paxilline, and iberiotoxin. In single-channel experiments, depolarization resulted in an increase in open channel probability ( Po) of KCa3.1, with no increase in channel number. The voltage modulation of Powas an increasing monotonic function of voltage. In the absence of elevated Ca2+, voltage was ineffective at inducing channel activity in whole cell and single-channel experiments. These data indicate that KCa3.1 in HEL cells displays a unique form of voltage dependence modulating Po.

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Ohya, Susumu, Junko Kajikuri, Kyoko Endo, Hiroaki Kito, and Miki Matsui. "KCa1.1 K+ Channel Inhibition Overcomes Resistance to Antiandrogens and Doxorubicin in a Human Prostate Cancer LNCaP Spheroid Model." International Journal of Molecular Sciences 22, no. 24 (December 17, 2021): 13553. http://dx.doi.org/10.3390/ijms222413553.

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Several types of K+ channels play crucial roles in tumorigenicity, stemness, invasiveness, and drug resistance in cancer. Spheroid formation of human prostate cancer (PC) LNCaP cells with ultra-low attachment surface cultureware induced the up-regulation of cancer stem cell markers, such as NANOG, and decreased the protein degradation of the Ca2+-activated K+ channel KCa1.1 by down-regulating the E3 ubiquitin ligase, FBXW7, compared with LNCaP monolayers. Accordingly, KCa1.1 activator-induced hyperpolarizing responses were larger in isolated cells from LNCaP spheroids. The pharmacological inhibition of KCa1.1 overcame the resistance of LNCaP spheroids to antiandrogens and doxorubicin (DOX). The protein expression of androgen receptors (AR) was significantly decreased by LNCaP spheroid formation and reversed by KCa1.1 inhibition. The pharmacological and genetic inhibition of MDM2, which may be related to AR protein degradation in PC stem cells, revealed that MDM2 was responsible for the acquisition of antiandrogen resistance in LNCaP spheroids, which was overcome by KCa1.1 inhibition. Furthermore, a member of the multidrug resistance-associated protein subfamily of ABC transporters, MRP5 was responsible for the acquisition of DOX resistance in LNCaP spheroids, which was also overcome by KCa1.1 inhibition. Collectively, the present results suggest the potential of KCa1.1 in LNCaP spheroids, which mimic PC stem cells, as a therapeutic target for overcoming antiandrogen- and DOX-resistance in PC cells.

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Rehak, Renata, Theodore M. Bartoletti, Jordan D. T. Engbers, Geza Berecki, Ray W. Turner, and Gerald W. Zamponi. "Low Voltage Activation of KCa1.1 Current by Cav3-KCa1.1 Complexes." PLoS ONE 8, no. 4 (April 23, 2013): e61844. http://dx.doi.org/10.1371/journal.pone.0061844.

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Sones, WR, N. Leblanc, and IA Greenwood. "Inhibition of vascular calcium-gated chloride currents by blockers of KCa1.1, but not by modulators of KCa2.1 or KCa2.3 channels." British Journal of Pharmacology 158, no. 2 (July 23, 2009): 521–31. http://dx.doi.org/10.1111/j.1476-5381.2009.00332.x.

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Xin, Wenkuan, Qiuping Cheng, Rupal P. Soder, Eric S. Rovner, and Georgi V. Petkov. "Constitutively active phosphodiesterase activity regulates urinary bladder smooth muscle function: critical role of KCa1.1 channel." American Journal of Physiology-Renal Physiology 303, no. 9 (November 1, 2012): F1300—F1306. http://dx.doi.org/10.1152/ajprenal.00351.2012.

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Pharmacological blockade of cyclic nucleotide phosphodiesterase (PDE) can relax human urinary bladder smooth muscle (UBSM); however, the underlying cellular mechanism is unknown. In this study, we investigated the effects of PDE pharmacological blockade on human UBSM excitability, spontaneous and nerve-evoked contractility, and determined the underlying cellular mechanism mediating these effects. Patch-clamp electrophysiological experiments showed that 3-isobutyl-1-methylxanthine (10 μM), a nonselective PDE inhibitor, caused ∼3.6-fold increase in the transient KCa1.1 channel current frequency and ∼2.5-fold increase in the spontaneous transient hyperpolarization frequency in UBSM-isolated cells. PDE blockade also caused ∼5.6-mV hyperpolarization of the UBSM cell membrane potential. Blocking the KCa1.1 channels with paxilline abolished the spontaneous transient hyperpolarization and the hyperpolarization effect of PDE blockade on the UBSM cell membrane potential. Live cell Ca2+-imaging experiments showed that PDE blockade significantly decreased the global intracellular Ca2+ levels. Attenuation of PDE activity significantly reduced spontaneous phasic contraction amplitude, muscle force integral, duration, frequency, and muscle tone of human UBSM isolated strips. Blockade of PDE also significantly reduced the contraction amplitude, muscle force integral, and duration of the nerve-evoked contractions induced by 20-Hz electrical field stimulation. Pharmacological inhibition of KCa1.1 channels abolished the relaxation effects of PDE blockade on both spontaneous and nerve-evoked contractions in human UBSM-isolated strips. Our data provide strong evidence that in human UBSM PDE is constitutively active, thus maintaining spontaneous UBSM contractility. PDE blockade causes relaxation of human UBSM by increasing transient KCa1.1 channel current activity, hyperpolarizing cell membrane potential, and decreasing the global intracellular Ca2+.

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Li, Bai-Yan, Patricia Glazebrook, Diana L. Kunze, and John H. Schild. "KCa1.1 channel contributes to cell excitability in unmyelinated but not myelinated rat vagal afferents." American Journal of Physiology-Cell Physiology 300, no. 6 (June 2011): C1393—C1403. http://dx.doi.org/10.1152/ajpcell.00278.2010.

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High conductance calcium-activated potassium (BKCa) channels can modulate cell excitability and neurotransmitter release at synaptic and afferent terminals. BKCa channels are present in primary afferents of most, if not, all internal organs and are an intriguing target for pharmacological manipulation of visceral sensation. Our laboratory has a long-standing interest in the neurophysiological differences between myelinated and unmyelinated visceral afferent function. Here, we seek to determine whether there is a differential distribution of BKCa channels in myelinated and unmyelinated vagal afferents. Immunocytochemistry studies with double staining for the BK-type KCa1.1 channel protein and isolectin B4 (IB4), a reliable marker of unmyelinated peripheral afferents, reveal a pattern of IB4 labeling that strongly correlates with the expression of the KCa1.1 channel protein. Measures of cell size and immunostaining intensity for KCa1.1 and IB4 cluster into two statistically distinct ( P < 0.05) populations of cells. Smaller diameter neurons most often presented with strong IB4 labeling and are presumed to be unmyelinated ( n = 1,390) vagal afferents. Larger diameter neurons most often lacked or exhibited a very weak IB4 labeling and are presumed to be myelinated ( n = 58) vagal afferents. Complimentary electrophysiological studies reveal that the BKCa channel blockers charybdotoxin (ChTX) and iberiotoxin (IbTX) bring about a comparable elevation in excitability and action potential widening in unmyelinated neurons but had no effect on the excitability of myelinated vagal afferents. This study is the first to demonstrate using combined immunohistochemical and electrophysiological techniques that KCa1.1 channels are uniquely expressed in unmyelinated C-type vagal afferents and do not contribute to the dynamic discharge characteristics of myelinated A-type vagal afferents. This unique functional distribution of BK-type KCa channels may provide an opportunity for afferent selective pharmacological intervention across a wide range of visceral pathophysiologies, particularly those with a reflexogenic etiology and pain.

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Orfali, Razan, and Nora Albanyan. "Ca2+-Sensitive Potassium Channels." Molecules 28, no. 2 (January 16, 2023): 885. http://dx.doi.org/10.3390/molecules28020885.

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The Ca2+ ion is used ubiquitously as an intracellular signaling molecule due to its high external and low internal concentration. Many Ca2+-sensing ion channel proteins have evolved to receive and propagate Ca2+ signals. Among them are the Ca2+-activated potassium channels, a large family of potassium channels activated by rises in cytosolic calcium in response to Ca2+ influx via Ca2+-permeable channels that open during the action potential or Ca2+ release from the endoplasmic reticulum. The Ca2+ sensitivity of these channels allows internal Ca2+ to regulate the electrical activity of the cell membrane. Activating these potassium channels controls many physiological processes, from the firing properties of neurons to the control of transmitter release. This review will discuss what is understood about the Ca2+ sensitivity of the two best-studied groups of Ca2+-sensitive potassium channels: large-conductance Ca2+-activated K+ channels, KCa1.1, and small/intermediate-conductance Ca2+-activated K+ channels, KCa2.x/KCa3.1.

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Matos, J. E., M. Sausbier, G. Beranek, U. Sausbier, P. Ruth, and J. Leipziger. "Role of cholinergic-activated KCa1.1 (BK), KCa3.1 (SK4) and KV7.1 (KCNQ1) channels in mouse colonic Cl?secretion." Acta Physiologica 189, no. 3 (March 2007): 251–58. http://dx.doi.org/10.1111/j.1748-1716.2006.01646.x.

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Harron, Scott A., Christina M. Clarke, Christina L. Jones, Dominique Babin-Muise, and Elizabeth A. Cowley. "Volume regulation in the human airway epithelial cell line Calu-3." Canadian Journal of Physiology and Pharmacology 87, no. 5 (May 2009): 337–46. http://dx.doi.org/10.1139/y09-009.

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Cells regulate their volume in response to changes in the osmolarity of both their extracellular and their intracellular environments. We investigated the ability of the human airway epithelial cell line Calu-3 to respond to changes in extracellular osmolarity. Although switching Calu-3 cells from an isosmotic to a hyperosmotic environment resulted in cell shrinkage, there was no compensatory mechanism for the cells to return to their original volume. In contrast, switching to a hyposmotic environment resulted in an initial cell swelling response, followed by a regulatory volume decrease (RVD). Pharmacologic studies demonstrate that the voltage-activated K+ channels Kv4.1 and (or) Kv4.3 play a crucial role in mediating this RVD response, and we demonstrated expression of these channel types at the mRNA and protein levels. Furthermore, inhibition of the large- and intermediate-conductance Ca2+-activated K+ channels KCa1.1 (maxi-K) and KCa3.1 (hIK) also implicated these channels as playing a role in volume recovery in Calu-3 cells. This report describes the nature of volume regulation in the widely used model cell line Calu-3.

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Golder, Francis J., Scott Dax, Santhosh M. Baby, Ryan Gruber, Toshinori Hoshi, Courtney Ideo, Andrew Kennedy, et al. "Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator." Anesthesiology 123, no. 5 (November 1, 2015): 1093–104. http://dx.doi.org/10.1097/aln.0000000000000844.

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Abstract Background The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator. Methods The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve–transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays. Results GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1−/− mice lacking the pore-forming α-subunit of the KCa1.1 channel. Conclusions GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

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Larsen, Casper K., Iben S. Jensen, Mads V. Sorensen, Pauline I. de Bruijn, Markus Bleich, Helle A. Praetorius, and Jens Leipziger. "Hyperaldosteronism after decreased renal K+ excretion in KCNMB2 knockout mice." American Journal of Physiology-Renal Physiology 310, no. 10 (May 15, 2016): F1035—F1046. http://dx.doi.org/10.1152/ajprenal.00010.2016.

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The kidney is the primary organ ensuring K+ homeostasis. K+ is secreted into the urine in the distal tubule by two mechanisms: by the renal outer medullary K+ channel (Kir1.1) and by the Ca2+-activated K+ channel (KCa1.1). Here, we report a novel knockout mouse of the β2-subunit of the KCa1.1 channel (KCNMB2), which displays hyperaldosteronism after decreased renal K+ excretion. KCNMB2−/− mice displayed hyperaldosteronism, normal plasma K+ concentration, and produced dilute urine with decreased K+ concentration. The normokalemia indicated that hyperaldosteronism did not result from primary aldosteronism. Activation of the renin-angiotensin-aldosterone system was also ruled out as renal renin mRNA expression was reduced in KCNMB2−/− mice. Renal K+ excretion rates were similar in the two genotypes; however, KCNMB2−/− mice required elevated plasma aldosterone to achieve K+ balance. Blockade of the mineralocorticoid receptor with eplerenone triggered mild hyperkalemia and unmasked reduced renal K+ excretion in KCNMB2−/− mice. Knockout mice for the α-subunit of the KCa1.1 channel (KCNMA1−/− mice) have hyperaldosteronism, are hypertensive, and lack flow-induced K+ secretion. KCNMB2−/− mice share the phenotypic traits of normokalemia and hyperaldosteronism with KCNMA1−/− mice but were normotensive and displayed intact flow-induced K+ secretion. Despite elevated plasma aldosterone, KNCMB2−/− mice did not display salt-sensitive hypertension and were able to decrease plasma aldosterone on a high-Na+ diet, although plasma aldosterone remained elevated in KCNMB2−/− mice. In summary, KCNMB2−/− mice have a reduced ability to excrete K+ into the urine but achieve K+ balance through an aldosterone-mediated, β2-independent mechanism. The phenotype of KCNMB2 mice was similar but milder than the phenotype of KCNMA1−/− mice.

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Beeton, Christine. "KCa1.1 channels as therapeutic targets for rheumatoid arthritis." Expert Opinion on Therapeutic Targets 21, no. 12 (October 31, 2017): 1077–81. http://dx.doi.org/10.1080/14728222.2017.1398234.

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Brizzi, Antonella, Alfonso Trezza, Ottavia Spiga, Samuele Maramai, Francesco Scorzelli, Simona Saponara, and Fabio Fusi. "2-Hydroxy-5-(3,5,7-trihydroxy-4-oxo-4H-chromen-2-yl)phenyl (E)-3-(4-hydroxy-3-methoxyphenyl)acrylate: Synthesis, In Silico Analysis and In Vitro Pharmacological Evaluation." Molbank 2021, no. 3 (July 23, 2021): M1258. http://dx.doi.org/10.3390/m1258.

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Quercetin and ferulic acid are two phytochemicals extensively represented in the plant kingdom and daily consumed in considerable amounts through diets. Due to a common phenolic structure, these two molecules share several pharmacological properties, e.g., antioxidant and free radical scavenging, anti-cancer, anti-inflammatory, anti-arrhythmic, and vasorelaxant. The aim of the present work was the combination of the two molecules in a single chemical entity, conceivably endowed with more efficacious vasorelaxant activity. Preliminary in silico studies herein described suggested that the new hybrid compound bound spontaneously and with high affinity on the KCa1.1 channel. Thus, the synthesis of the 3′-ferulic ester derivative of quercetin was achieved and its structure confirmed by 1H- and 13C-NMR spectra, HSQC and HMBC experiments, mass spectrometry, and elementary analysis. The effect of the new hybrid compound on vascular KCa1.1 and CaV1.2 channels revealed a partial loss of the stimulatory activity that characterizes the parent compound quercetin. Therefore, further studies are necessary to identify a better strategy to improve the vascular properties of this flavonoid.

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Mészáros, Beáta, Agota Csoti, Tibor G. Szanto, Andrea Telek, Katalin Kovács, Agnes Toth, Julianna Volkó, and Gyorgy Panyi. "The hEag1 K+ Channel Inhibitor Astemizole Stimulates Ca2+ Deposition in SaOS-2 and MG-63 Osteosarcoma Cultures." International Journal of Molecular Sciences 23, no. 18 (September 11, 2022): 10533. http://dx.doi.org/10.3390/ijms231810533.

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The hEag1 (Kv10.1) K+ channel is normally found in the brain, but it is ectopically expressed in tumor cells, including osteosarcoma. Based on the pivotal role of ion channels in osteogenesis, we tested whether pharmacological modulation of hEag1 may affect osteogenic differentiation of osteosarcoma cell lines. Using molecular biology (RT-PCR), electrophysiology (patch-clamp) and pharmacology (astemizole sensitivity, IC50 = 0.135 μM) we demonstrated that SaOS-2 osteosarcoma cells also express hEag1 channels. SaOS-2 cells also express to KCa1.1 K+ channels as shown by mRNA expression and paxilline sensitivity of the current. The inhibition of hEag1 (2 μM astemizole) or KCa1.1 (1 mM TEA) alone did not induce Ca2+ deposition in SaOS-2 cultures, however, these inhibitors, at identical concentrations, increased Ca2+ deposition evoked by the classical or pathological (inorganic phosphate, Pi) induction pathway without causing cytotoxicity, as reported by three completer assays (LDH release, MTT assay and SRB protein assay). We observed a similar effect of astemizole on Ca2+ deposition in MG-63 osteosarcoma cultures as well. We propose that the increase in the osteogenic stimuli-induced mineral matrix formation of osteosarcoma cell lines by inhibiting hEag1 may be a useful tool to drive terminal differentiation of osteosarcoma.

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Sørensen, Mads V., Joana E. Matos, Matthias Sausbier, Ulrike Sausbier, Peter Ruth, Helle A. Praetorius, and Jens Leipziger. "Aldosterone increases KCa1.1 (BK) channel-mediated colonic K+secretion." Journal of Physiology 586, no. 17 (September 1, 2008): 4251–64. http://dx.doi.org/10.1113/jphysiol.2008.156968.

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Denes Petho, Zoltan, Andras Balajthy, Almos Klekner, Laszlo Bognar, Zoltan Varga, and Gyorgy Panyi. "KCa1.1 Channel Auxiliary Beta Subunit Composition in Glioblastoma Multiforme." Biophysical Journal 112, no. 3 (February 2017): 546a. http://dx.doi.org/10.1016/j.bpj.2016.11.2952.

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Carullo, Gabriele, Simona Saponara, Amer Ahmed, Beatrice Gorelli, Sarah Mazzotta, Alfonso Trezza, Beatrice Gianibbi, Giuseppe Campiani, Fabio Fusi, and Francesca Aiello. "Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels." Marine Drugs 20, no. 8 (August 13, 2022): 515. http://dx.doi.org/10.3390/md20080515.

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Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a CaV1.2 channel blocker and a KCa1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the CaV1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the CaV1.2 channel blockade and KCa1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy.

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Engbers, Jordan DT, Gerald W. Zamponi, and Ray W. Turner. "Modeling interactions between voltage-gated Ca2+channels and KCa1.1 channels." Channels 7, no. 6 (November 2, 2013): 524–29. http://dx.doi.org/10.4161/chan.25867.

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Ortiz, Mario I., Raquel Cariño-Cortés, Víctor M. Muñoz-Pérez, Carlo Eduardo Medina-Solís, and Gilberto Castañeda-Hernández. "Citral inhibits the nociception in the rat formalin test: effect of metformin and blockers of opioid receptor and the NO-cGMP-K⁺ channel pathway." Canadian Journal of Physiology and Pharmacology 100, no. 4 (April 2022): 306–13. http://dx.doi.org/10.1139/cjpp-2021-0458.

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The objective of the present study was to scrutinize the effect of nitric oxide (NO), cyclic GMP (cGMP), potassium channel blockers, and metformin on the citral-produced peripheral antinociception. The rat paw 1% formalin test was used to assess nociception and antinociception. Rats were treated with local peripheral administration of citral (10–100 µg/paw). The antinociception of citral (100 µg/paw) was evaluated with and without the local pretreatment of naloxone, NG-L-nitro-arginine methyl ester (L-NAME, a NO synthesis inhibitor), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ, a soluble guanylyl cyclase inhibitor), metformin, opioid receptors antagonists, and K+ channel blockers. Injection of citral in the rat paw significantly decreased the nociceptive effect of formalin administration during the two phases of the test. Local pretreatment of the paws with L-NAME and ODQ did not reduced the citral-induced antinociception. Glipizide or glibenclamide (Kir6.1-2; ATP-sensitive K+ channel blockers), tetraethylammonium or 4-aminopyridine (KV; voltage-gated K+ channel blockers), charybdotoxin (KCa1.1; big conductance calcium-activated K+ channel blocker), apamin (KCa2.1-3; small conductance Ca2+-activated K+ channel antagonist), or metformin, but not the opioid antagonists, reduced the antinociception of citral. Citral produced peripheral antinociception during both phases of the formalin test. These effects were due to the activation of K+ channels and a biguanide-dependent mechanism.

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Romanenko, Victor G., Kurt S. Roser, James E. Melvin, and Ted Begenisich. "The role of cell cholesterol and the cytoskeleton in the interaction between IK1 and maxi-K channels." American Journal of Physiology-Cell Physiology 296, no. 4 (April 2009): C878—C888. http://dx.doi.org/10.1152/ajpcell.00438.2008.

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Recently, we demonstrated a novel interaction between large-conductance (maxi-K or KCa1.1) and intermediate-conductance (IK1 or KCa3.1) Ca2+-activated K channels: activation of IK1 channels causes the inhibition of maxi-K activity (Thompson J and Begenisich T. J Gen Physiol 127: 159–169, 2006). Here we show that the interaction between these two channels can be regulated by the membrane cholesterol level in parotid acinar cells. Depletion of cholesterol using methyl-β-cyclodextrin weakened, while cholesterol enrichment increased, the ability of IK1 activation to inhibit maxi-K channels. Cholesterol's stereoisomer, epicholesterol, was unable to substitute for cholesterol in the interaction between the two K channels, suggesting a specific cholesterol-protein interaction. This suggestion was strengthened by the results of experiments in which cholesterol was replaced by coprostanol and epicoprostanol. These two sterols have nearly identical effects on membrane physical properties and cholesterol-rich microdomain stability, but had very different effects on the IK1/maxi-K interaction. In addition, the IK1/maxi-K interaction was unaltered in cells lacking caveolin, the protein essential for formation and stability of caveolae. Finally, disruption of the actin cytoskeleton restored the IK1-induced maxi-K inhibition that was lost with cell cholesterol depletion, demonstrating the importance of an intact cytoskeleton for the cholesterol-dependent regulation of the IK1/maxi-K interaction.

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Gonzalez-Perez, Vivian, Manu Ben Johny, Xiao-Ming Xia, and Christopher J. Lingle. "Regulatory γ1 subunits defy symmetry in functional modulation of BK channels." Proceedings of the National Academy of Sciences 115, no. 40 (September 17, 2018): 9923–28. http://dx.doi.org/10.1073/pnas.1804560115.

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Structural symmetry is a hallmark of homomeric ion channels. Nonobligatory regulatory proteins can also critically define the precise functional role of such channels. For instance, the pore-forming subunit of the large conductance voltage and calcium-activated potassium (BK, Slo1, or KCa1.1) channels encoded by a single KCa1.1 gene assembles in a fourfold symmetric fashion. Functional diversity arises from two families of regulatory subunits, β and γ, which help define the range of voltages over which BK channels in a given cell are activated, thereby defining physiological roles. A BK channel can contain zero to four β subunits per channel, with each β subunit incrementally influencing channel gating behavior, consistent with symmetry expectations. In contrast, a γ1 subunit (or single type of γ1 subunit complex) produces a functionally all-or-none effect, but the underlying stoichiometry of γ1 assembly and function remains unknown. Here we utilize two distinct and independent methods, a Forster resonance energy transfer-based optical approach and a functional reporter in single-channel recordings, to reveal that a BK channel can contain up to four γ1 subunits, but a single γ1 subunit suffices to induce the full gating shift. This requires that the asymmetric association of a single regulatory protein can act in a highly concerted fashion to allosterically influence conformational equilibria in an otherwise symmetric K+channel.

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Nayak, Tapan K., Ridhima Vij, Iva Bruhova, Jayasha Shandilya, and Anthony Auerbach. "Efficiency measures the conversion of agonist binding energy into receptor conformational change." Journal of General Physiology 151, no. 4 (January 11, 2019): 465–77. http://dx.doi.org/10.1085/jgp.201812215.

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Receptors alternate between resting↔active conformations that bind agonists with low↔high affinity. Here, we define a new agonist attribute, energy efficiency (η), as the fraction of ligand-binding energy converted into the mechanical work of the activation conformational change. η depends only on the resting/active agonist-binding energy ratio. In a plot of activation energy versus binding energy (an “efficiency” plot), the slope gives η and the y intercept gives the receptor’s intrinsic activation energy (without agonists; ΔG0). We used single-channel electrophysiology to estimate η for eight different agonists and ΔG0 in human endplate acetylcholine receptors (AChRs). From published equilibrium constants, we also estimated η for agonists of KCa1.1 (BK channels) and muscarinic, γ-aminobutyric acid, glutamate, glycine, and aryl-hydrocarbon receptors, and ΔG0 for all of these except KCa1.1. Regarding AChRs, η is 48–56% for agonists related structurally to acetylcholine but is only ∼39% for agonists related to epibatidine; ΔG0 is 8.4 kcal/mol in adult and 9.6 kcal/mol in fetal receptors. Efficiency plots for all of the above receptors are approximately linear, with η values between 12% and 57% and ΔG0 values between 2 and 12 kcal/mol. Efficiency appears to be a general attribute of agonist action at receptor binding sites that is useful for understanding binding mechanisms, categorizing agonists, and estimating concentration–response relationships.

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Sørensen, Mads V., Matthias Sausbier, Peter Ruth, Ursula Seidler, Brigitte Riederer, Helle A. Praetorius, and Jens Leipziger. "Adrenaline-induced colonic K+secretion is mediated by KCa1.1 (BK) channels." Journal of Physiology 588, no. 10 (May 14, 2010): 1763–77. http://dx.doi.org/10.1113/jphysiol.2009.181933.

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Bentzen, Bo H., Antonio Nardi, Søren P. Olesen, and Morten Grunnet. "Novel large conductance calcium- and voltage-activated K+ channel (KCa1.1) modulator." Journal of Molecular and Cellular Cardiology 42, no. 6 (June 2007): S17. http://dx.doi.org/10.1016/j.yjmcc.2007.03.048.

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Asano, Shinichi, Johnathan D. Tune, and Gregory M. Dick. "Bisphenol A activates Maxi-K (KCa1.1) channels in coronary smooth muscle." British Journal of Pharmacology 160, no. 1 (March 19, 2010): 160–70. http://dx.doi.org/10.1111/j.1476-5381.2010.00687.x.

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Ortiz, Mario I., Raquel Cariño-Cortés, and Gilberto Castañeda-Hernández. "Participation of the opioid receptor – nitric oxide – cGMP – K+ channel pathway in the peripheral antinociceptive effect of nalbuphine and buprenorphine in rats." Canadian Journal of Physiology and Pharmacology 98, no. 11 (November 2020): 753–62. http://dx.doi.org/10.1139/cjpp-2020-0104.

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The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats (180–220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50–200 μg/paw) or buprenorphine (1–5 μg/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis (NG-nitro-l-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the Kir6.1–2, ATP-sensitive K+ channel inhibitors (glibenclamide and glipizide), by the KCa2.1–3, small conductance Ca2+-activated K+ channel blocker (apamin), by the KCa1.1, large conductance Ca2+-activated K+ channel blocker (charybdotoxin), and by the KV, voltage-dependent K+ channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs.

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Steffensen, Simon G. Comerma, Judit Prat Duran, Susie Mogensen, Rafael S. Fais, Estefano Pinilla, and Prof Ulf Simonsen. "Erectile dysfunction and altered contribution of kCa1.1 and kCa2.3 channels in penile tissue of type-2 diabetic db/db mice." Journal of Sexual Medicine 19, no. 11 (November 2022): S1. http://dx.doi.org/10.1016/j.jsxm.2022.08.075.

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32

Almássy, János, and Péter P. Nánási. "Brief structural insight into the allosteric gating mechanism of BK (Slo1) channel." Canadian Journal of Physiology and Pharmacology 97, no. 6 (June 2019): 498–502. http://dx.doi.org/10.1139/cjpp-2018-0516.

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The big conductance Ca2+-dependent K+ channel, also known as BK, MaxiK, Slo1, or KCa1.1, is a ligand- and voltage-gated K+ channel. Although structure-function studies of the past decades, involving mutagenesis and electrophysiological measurements, revealed fine details of the mechanism of BK channel gating, the exact molecular details remained unknown until the quaternary structure of the protein has been solved at a resolution of 3.5 Å using cryo-electron microscopy. In this short review, we are going to summarize these results and interpret the gating model of the BK channel in the light of the recent structural results.

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Kloza, Baranowska-Kuczko, Toczek, Kusaczuk, Sadowska, Kasacka, and Kozłowska. "Modulation of Cardiovascular Function in Primary Hypertension in Rat by SKA-31, an Activator of KCa2.x and KCa3.1 Channels." International Journal of Molecular Sciences 20, no. 17 (August 23, 2019): 4118. http://dx.doi.org/10.3390/ijms20174118.

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The aim of this study was to investigate the hemodynamic effects of SKA-31, an activator of the small (KCa2.x) and intermediate (KCa3.1) conductance calcium-activated potassium channels, and to evaluate its influence on endothelium-derived hyperpolarization (EDH)-KCa2.3/KCa3.1 type relaxation in isolated endothelium-intact small mesenteric arteries (sMAs) from spontaneously hypertensive rats (SHRs). Functional in vivo and in vitro experiments were performed on SHRs or their normotensive controls, Wistar-Kyoto rats (WKY). SKA-31 (1, 3 and 10 mg/kg) caused a brief decrease in blood pressure and bradycardia in both SHR and WKY rats. In phenylephrine-pre-constricted sMAs of SHRs, SKA-31 (0.01–10 µM)-mediated relaxation was reduced and SKA-31 potentiated acetylcholine-evoked endothelium-dependent relaxation. Endothelium denudation and inhibition of nitric oxide synthase (eNOS) and cyclooxygenase (COX) by the respective inhibitors l-NAME or indomethacin, attenuated SKA-31-mediated vasorelaxation. The inhibition of KCa3.1, KCa2.3, KIR and Na+/K+-ATPase by TRAM-34, UCL1684, Ba2+ and ouabain, respectively, reduced the potency and efficacy of the EDH-response evoked by SKA-31. The mRNA expression of eNOS, prostacyclin synthase, KCa2.3, KCa3.1 and KIR were decreased, while Na+/K+-ATPase expression was increased. Collectively, SKA-31 promoted hypotension and vasodilatation, potentiated agonist-stimulated vasodilation, and maintained KCa2.3/KCa3.1-EDH-response in sMAs of SHR with downstream signaling that involved KIR and Na+/K+-ATPase channels. In view of the importance of the dysfunction of endothelium-mediated vasodilatation in the mechanism of hypertension, application of activators of KCa2.3/KCa3.1 channels such as SKA-31 seem to be a promising avenue in pharmacotherapy of hypertension.

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Ohya, Susumu, Yuka Fukuyo, Hiroaki Kito, Rina Shibaoka, Miki Matsui, Hiroki Niguma, Yasuhiro Maeda, et al. "Upregulation of KCa3.1 K+ channel in mesenteric lymph node CD4+ T lymphocytes from a mouse model of dextran sodium sulfate-induced inflammatory bowel disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 306, no. 10 (May 15, 2014): G873—G885. http://dx.doi.org/10.1152/ajpgi.00156.2013.

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The intermediate-conductance Ca2+-activated K+ channel KCa3.1/KCNN4 plays an important role in the modulation of Ca2+ signaling through the control of the membrane potential in T lymphocytes. Here, we study the involvement of KCa3.1 in the enlargement of the mesenteric lymph nodes (MLNs) in a mouse model of inflammatory bowel disease (IBD). The mouse model of IBD was prepared by exposing male C57BL/6J mice to 5% dextran sulfate sodium for 7 days. Inflammation-induced changes in KCa3.1 activity and the expressions of KCa3.1 and its regulators in MLN CD4+ T lymphocytes were monitored by real-time PCR, Western blot, voltage-sensitive dye imaging, patch-clamp, and flow cytometric analyses. Concomitant with an upregulation of KCa3.1a and nucleoside diphosphate kinase B (NDPK-B), a positive KCa3.1 regulator, an increase in KCa3.1 activity was observed in MLN CD4+ T lymphocytes in the IBD model. Pharmacological blockade of KCa3.1 elicited the following results: 1) a significant decrease in IBD disease severity, as assessed by diarrhea, visible fecal blood, inflammation, and crypt damage of the colon and MLN enlargement compared with control mice, and 2) the restoration of the expression levels of KCa3.1a, NDPK-B, and Th1 cytokines in IBD model MLN CD4+ T lymphocytes. These findings suggest that the increase in KCa3.1 activity induced by the upregulation of KCa3.1a and NDPK-B may be involved in the pathogenesis of IBD by mediating the enhancement of the proliferative response in MLN CD4+ T lymphocyte and, therefore, that the pharmacological blockade of KCa3.1 may decrease the risk of IBD.

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Gonzalez-Perez, Vivian, and Christopher J. Lingle. "Regulation of BK Channels by Beta and Gamma Subunits." Annual Review of Physiology 81, no. 1 (February 10, 2019): 113–37. http://dx.doi.org/10.1146/annurev-physiol-022516-034038.

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Ca2+- and voltage-gated K+ channels of large conductance (BK channels) are expressed in a diverse variety of both excitable and inexcitable cells, with functional properties presumably uniquely calibrated for the cells in which they are found. Although some diversity in BK channel function, localization, and regulation apparently arises from cell-specific alternative splice variants of the single pore–forming α subunit ( KCa1.1, Kcnma1, Slo1) gene, two families of regulatory subunits, β and γ, define BK channels that span a diverse range of functional properties. We are just beginning to unravel the cell-specific, physiological roles served by BK channels of different subunit composition.

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Thompson, Jill, and Ted Begenisich. "Membrane-delimited Inhibition of Maxi-K Channel Activity by the Intermediate Conductance Ca2+-activated K Channel." Journal of General Physiology 127, no. 2 (January 17, 2006): 159–69. http://dx.doi.org/10.1085/jgp.200509457.

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The complexity of mammalian physiology requires a diverse array of ion channel proteins. This diversity extends even to a single family of channels. For example, the family of Ca2+-activated K channels contains three structural subfamilies characterized by small, intermediate, and large single channel conductances. Many cells and tissues, including neurons, vascular smooth muscle, endothelial cells, macrophages, and salivary glands express more than a single class of these channels, raising questions about their specific physiological roles. We demonstrate here a novel interaction between two types of Ca2+-activated K channels: maxi-K channels, encoded by the KCa1.1 gene, and IK1 channels (KCa3.1). In both native parotid acinar cells and in a heterologous expression system, activation of IK1 channels inhibits maxi-K activity. This interaction was independent of the mode of activation of the IK1 channels: direct application of Ca2+, muscarinic receptor stimulation, or by direct chemical activation of the IK1 channels. The IK1-induced inhibition of maxi-K activity occurred in small, cell-free membrane patches and was due to a reduction in the maxi-K channel open probability and not to a change in the single channel current level. These data suggest that IK1 channels inhibit maxi-K channel activity via a direct, membrane-delimited interaction between the channel proteins. A quantitative analysis indicates that each maxi-K channel may be surrounded by four IK1 channels and will be inhibited if any one of these IK1 channels opens. This novel, regulated inhibition of maxi-K channels by activation of IK1 adds to the complexity of the properties of these Ca2+-activated K channels and likely contributes to the diversity of their functional roles.

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Iozzi, D., R. Schubert, V. U. Kalenchuk, A. Neri, G. Sgaragli, F. Fusi, and S. Saponara. "Quercetin relaxes rat tail main artery partlyviaa PKG-mediated stimulation of KCa1.1 channels." Acta Physiologica 208, no. 4 (March 25, 2013): 329–39. http://dx.doi.org/10.1111/apha.12083.

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38

Zhang, Jiao, Yau-Chi Chan, Jenny Chung-Yee Ho, Chung-Wah Siu, Qizhou Lian, and Hung-Fat Tse. "Regulation of cell proliferation of human induced pluripotent stem cell-derived mesenchymal stem cells via ether-à-go-go 1 (hEAG1) potassium channel." American Journal of Physiology-Cell Physiology 303, no. 2 (July 15, 2012): C115—C125. http://dx.doi.org/10.1152/ajpcell.00326.2011.

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The successful generation of a high yield of mesenchymal stem cells (MSCs) from human induced pluripotent stem cells (iPSCs) may represent an unlimited cell source with superior therapeutic benefits for tissue regeneration to bone marrow (BM)-derived MSCs. We investigated whether the differential expression of ion channels in iPSC-MSCs was responsible for their higher proliferation capacity than BM-MSCs. The expression of ion channels for K+, Na+, Ca2+, and Cl− was examined by RT-PCR. The electrophysiological properties of iPSC-MSCs and BM-MSCs were then compared by patch-clamp experiments to verify their functional roles. Significant mRNA expression of ion channel genes including KCa1.1, KCa3.1, KCNH1, Kir2.1, SCN9A, CACNA1C, and Clcn3 was observed in both human iPSC-MSCs and BM-MSCs, whereas Kir2.2 and Kir2.3 were only detected in human iPSC-MSCs. Five types of currents [big-conductance Ca2+-activated K+ current (BKCa), delayed rectifier K+ current ( IKDR), inwardly rectifying K+ current ( IKir), Ca2+-activated K+ current ( IKCa), and chloride current ( ICl)] were found in iPSC-MSCs (83%, 47%, 11%, 5%, and 4%, respectively) but only four of them (BKCa, IKDR, IKir, and IKCa) were identified in BM-MSCs (76%, 25%, 22%, and 11%, respectively). Cell proliferation was examined with MTT or bromodeoxyuridine assay, and doubling times were 2.66 and 3.72 days for iPSC-MSCs and BM-MSCs, respectively, showing a 1.4-fold discrepancy. Blockade of IKDR with short hairpin RNA or human ether-à-go-go 1 (hEAG1) channel blockers, 4-AP and astemizole, significantly reduced the rate of proliferation of human iPSC-MSCs. These treatments also decreased the rate of proliferation of human BM-MSCs albeit to a lesser extent. These findings demonstrate that the hEAG1 channel plays a crucial role in controlling the proliferation rate of human iPSC-MSCs and to a lesser extent in BM-MSCs.

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Kloza, Monika, Marta Baranowska-Kuczko, Olga Karpińska, and Hanna Kozłowska. "The role of small and intermediate conductance calcium-activated potassium channels in endothelial-dependent hyperpolarization in physiology and arterial hypertension." Postępy Higieny i Medycyny Doświadczalnej 73 (January 9, 2019): 1–14. http://dx.doi.org/10.5604/01.3001.0012.8388.

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The endothelium plays a crucial role in modulating vascular tone by synthesizing and releasing endothelium-derived relaxing factors, including nitric oxide (NO) and prostacyclin I2 (PGI2). Additionally, endothelium-dependent hyperpolarization (EDH) that is NO – and PGI2–independent participates in the relaxation of small-diameter blood vessels (<300 μm). EDH response is initiated by agonists (e.g. acetylcholine, bradykinin) – or shear stress – induced increase of calcium ions level in the endothelium and involves opening of the endothelial small (KCa2.3) and intermediate conductance (KCa3.1) calcium-activated potassium channels. The efflux of potassium ions could elicit the hyperpolarization of the surrounding myocytes by the activation of the inward-rectifier potassium ion channel (KIR) and/or Na+/K+-ATPase. The reduced release and/or bioavailability of NO, which is characteristic for endothelial dysfunction and may result in arterial hypertension, stimulate the generation of EDH signals, as a compensatory mechanism to maintain the endothelial control of vasodilator tone. The contribution of EDH in endothelium-dependent relaxation varies between vascular beds, animal and experimental model. In arterial hypertension the reduced expression/activity of KCa3.1 and KCa2.3 results in impaired vasorelaxation. Currently, the use of modulatory compounds (activators and inhibitors) of KCa3.1 and KCa2.3 as the potential therapeutic targets in cardiovascular diseases is under intensive investigation. It has already been known that application of activators of KCa3.1 and KCa2.3 potassium channels such (as SKA-31) can improve the EDH-type responses, the endothelial function and decrease mean arterial blood pressure. This may suggest the usefulness of these compounds in the treatment of arterial hypertension.

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Tarasov, Michail V., Marina F. Bystrova, Polina D. Kotova, Olga A. Rogachevskaja, Veronika Y. Sysoeva, and Stanislav S. Kolesnikov. "Calcium-gated K+ channels of the KCa1.1- and KCa3.1-type couple intracellular Ca2+ signals to membrane hyperpolarization in mesenchymal stromal cells from the human adipose tissue." Pflügers Archiv - European Journal of Physiology 469, no. 2 (December 27, 2016): 349–62. http://dx.doi.org/10.1007/s00424-016-1932-4.

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41

Tanner, Mark R., Zoltan Petho, Rajeev B. Tajhya, Redwan Huq, Frank T. Horrigan, Percio S. Gulco, and Christine Beeton. "KCa1.1 (BK) Channels on Fibroblast-Like Synoviocytes: A Novel Therapeutic Target for Rheumatoid Arthritis." Biophysical Journal 108, no. 2 (January 2015): 587a. http://dx.doi.org/10.1016/j.bpj.2014.11.3202.

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Morales, Patricia, Line Garneau, Hélène Klein, Marie-France Lavoie, Lucie Parent, and Rémy Sauvé. "Contribution of the KCa3.1 channel–calmodulin interactions to the regulation of the KCa3.1 gating process." Journal of General Physiology 142, no. 1 (June 24, 2013): 37–60. http://dx.doi.org/10.1085/jgp.201210933.

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The Ca2+-activated potassium channel of intermediate conductance, KCa3.1, is now emerging as a therapeutic target for a large variety of health disorders. The Ca2+ sensitivity of KCa3.1 is conferred by the Ca2+-binding protein calmodulin (CaM), with the CaM C-lobe constitutively bound to an intracellular domain of the channel C terminus. It was proposed on the basis of the crystal structure obtained for the C-terminal region of the rat KCa2.2 channel (rSK2) with CaM that the binding of Ca2+ to the CaM N-lobe results in CaM interlocking the C-terminal regions of two adjacent KCa3.1 subunits, leading to the formation of a dimeric structure. A study was thus undertaken to identify residues of the CaM N-lobe–KCa3.1 complex that either contribute to the channel activation process or control the channel open probability at saturating Ca2+ (Pomax). A structural homology model of the KCa3.1–CaM complex was first generated using as template the crystal structure of the C-terminal region of the rat KCa2.2 channel with CaM. This model was confirmed by cross-bridging residues R362 of KCa3.1 and K75 of CaM. Patch-clamp experiments were next performed, demonstrating that the solvation energy of the residue at position 367 in KCa3.1 is a key determinant to the channel Pomax and deactivation time toff. Mutations of residues M368 and Q364 predicted to form anchoring points for CaM binding to KCa3.1 had little impact on either toff or Pomax. Finally, our results show that channel activation depends on electrostatic interactions involving the charged residues R362 and E363, added to a nonpolar energy contribution coming from M368. We conclude that electrostatic interactions involving residues R362 and E363 and hydrophobic effects at M368 play a prominent role in KCa3.1 activation, whereas hydrophobic interactions at S367 are determinant to the stability of the CaM–KCa3.1 complex throughout gating.

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Suzuki, Yoshiaki, Hisao Yamamura, Susumu Ohya, and Yuji Imaizumi. "Direct molecular interaction of caveolin-3 with KCa1.1 channel in living HEK293 cell expression system." Biochemical and Biophysical Research Communications 430, no. 3 (January 2013): 1169–74. http://dx.doi.org/10.1016/j.bbrc.2012.12.015.

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Sørensen, Mads V., Anne B. Strandsby, Casper K. Larsen, Helle A. Praetorius, and Jens Leipziger. "The secretory KCa1.1 channel localises to crypts of distal mouse colon: functional and molecular evidence." Pflügers Archiv - European Journal of Physiology 462, no. 5 (August 6, 2011): 745–52. http://dx.doi.org/10.1007/s00424-011-1000-z.

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45

Hu, Xueyou, Teresina Laragione, Liang Sun, Shyny Koshy, Karlie R. Jones, Iskander I. Ismailov, Patricia Yotnda, Frank T. Horrigan, Pércio S. Gulko, and Christine Beeton. "KCa1.1 Potassium Channels Regulate Key Proinflammatory and Invasive Properties of Fibroblast-like Synoviocytes in Rheumatoid Arthritis." Journal of Biological Chemistry 287, no. 6 (November 10, 2011): 4014–22. http://dx.doi.org/10.1074/jbc.m111.312264.

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Shi, Lijun, Hanmeng Zhang, Yu Chen, Yujia Liu, Ni Lu, Tengteng Zhao, and Lubo Zhang. "Chronic exercise normalizes changes in Cav1.2 and KCa1.1 channels in mesenteric arteries from spontaneously hypertensive rats." British Journal of Pharmacology 172, no. 7 (January 23, 2015): 1846–58. http://dx.doi.org/10.1111/bph.13035.

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Bertrand, Jacques A., Martin Schicht, W. Daniel Stamer, David Baker, Joseph M. Sherwood, Elke Lütjen-Drecoll, David L. Selwood, and Darryl R. Overby. "The β4-Subunit of the Large-Conductance Potassium Ion Channel KCa1.1 Regulates Outflow Facility in Mice." Investigative Opthalmology & Visual Science 61, no. 3 (March 23, 2020): 41. http://dx.doi.org/10.1167/iovs.61.3.41.

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Tanner, Mark R., Michael W. Pennington, Teresina Laragione, Pércio S. Gulko, and Christine Beeton. "KCa1.1 channels regulate β 1 ‐integrin function and cell adhesion in rheumatoid arthritis fibroblast‐like synoviocytes." FASEB Journal 31, no. 8 (August 2017): 3309–20. http://dx.doi.org/10.1096/fj.201601097r.

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Carullo, Gabriele, Amer Ahmed, Alfonso Trezza, Ottavia Spiga, Antonella Brizzi, Simona Saponara, Fabio Fusi, and Francesca Aiello. "Design, synthesis and pharmacological evaluation of ester-based quercetin derivatives as selective vascular KCa1.1 channel stimulators." Bioorganic Chemistry 105 (December 2020): 104404. http://dx.doi.org/10.1016/j.bioorg.2020.104404.

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Xu, Wen-Xiao, Tao Ban, Lu-Qi Wang, Miao Zhao, Lei Yin, Guo Li, Hanying Chen, et al. "KCa1.1 β4-subunits are not responsible for iberiotoxin-resistance in baroreceptor neurons in adult male rats." International Journal of Cardiology 178 (January 2015): 184–87. http://dx.doi.org/10.1016/j.ijcard.2014.10.128.

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Journal articles on the topic 'Kca1.1'

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