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https://www.readbyqxmd.com/read/28696251/endothelin-1-stimulates-vasoconstriction-through-rab11a-serine-177-phosphorylation
#1
Xue Zhai, Marie D Leo, Jonathan H Jaggar
Rationale: Large-conductance calcium (Ca(2+))-activated potassium channels (BK) are composed of pore-forming BKα and auxiliary β1 subunits in arterial smooth muscle cells (myocytes). Vasoconstrictors, including endothelin-1 (ET-1), inhibit myocyte BK channels, leading to contraction, but mechanisms involved are unclear. Recent evidence indicates that BKα is primarily plasma membrane-localized, whereas the cellular location of β1 can be rapidly altered by Rab11A-positive recycling endosomes. Whether vasoconstrictors regulate the multi-subunit composition of surface BK channels to stimulate contraction is unclear...
July 10, 2017: Circulation Research
https://www.readbyqxmd.com/read/28600454/the-slo-w-path-to-identifying-the-mitochondrial-channels-responsible-for-ischemic-protection
#2
REVIEW
Charles Owen Smith, Keith Nehrke, Paul S Brookes
Mitochondria play an important role in tissue ischemia and reperfusion (IR) injury, with energetic failure and the opening of the mitochondrial permeability transition pore being the major causes of IR-induced cell death. Thus, mitochondria are an appropriate focus for strategies to protect against IR injury. Two widely studied paradigms of IR protection, particularly in the field of cardiac IR, are ischemic preconditioning (IPC) and volatile anesthetic preconditioning (APC). While the molecular mechanisms recruited by these protective paradigms are not fully elucidated, a commonality is the involvement of mitochondrial K(+) channel opening...
June 9, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28487419/membrane-depolarization-activates-bk-channels-through-rock-mediated-%C3%AE-1-subunit-surface-trafficking-to-limit-vasoconstriction
#3
M Dennis Leo, Xue Zhai, Padmapriya Muralidharan, Korah P Kuruvilla, Simon Bulley, Frederick A Boop, Jonathan H Jaggar
Membrane depolarization of smooth muscle cells (myocytes) in the small arteries that regulate regional organ blood flow leads to vasoconstriction. Membrane depolarization also activates large-conductance calcium (Ca(2+))-activated potassium (BK) channels, which limits Ca(2+) channel activity that promotes vasoconstriction, thus leading to vasodilation. We showed that in human and rat arterial myocytes, membrane depolarization rapidly increased the cell surface abundance of auxiliary BK β1 subunits but not that of the pore-forming BKα channels...
May 9, 2017: Science Signaling
https://www.readbyqxmd.com/read/28487418/science-signaling-podcast-for-9-may-2017-trafficking-of-bk-channel-subunits-in-arterial-myocytes
#4
Jonathan H Jaggar, Annalisa M VanHook
This Podcast features a conversation with Jonathan Jaggar, senior author of a Research Article that appears in the 9 May 2017 issue of Science Signaling, about trafficking of big potassium (BK) channel subunits in arterial myocytes. Depolarization of the arterial myocyte membrane causes a rise in intracellular calcium that stimulates the cell to contract, which leads to vasoconstriction. Membrane depolarization also activates BK channels, which allow potassium to flow out of the cell, thus repolarizing the membrane and promoting vasodilation...
May 9, 2017: Science Signaling
https://www.readbyqxmd.com/read/28428266/kca1-1-channels-regulate-%C3%AE-1-integrin-function-and-cell-adhesion-in-rheumatoid-arthritis-fibroblast-like-synoviocytes
#5
Mark R Tanner, Michael W Pennington, Teresina Laragione, Pércio S Gulko, Christine Beeton
Large-conductance calcium-activated potassium channel (KCa1.1; BK, Slo1, MaxiK, KCNMA1) is the predominant potassium channel expressed at the plasma membrane of fibroblast-like synoviocytes isolated from the synovium of patients with rheumatoid arthritis (RA-FLS). It is a critical regulator of RA-FLS migration and invasion and therefore represents an attractive target for the therapy of RA. However, the molecular mechanisms by which KCa1.1 regulates RA-FLS invasiveness have remained largely unknown. Here, we demonstrate that KCa1...
April 20, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28416688/knockout-of-the-lrrc26-subunit-reveals-a-primary-role-of-lrrc26-containing-bk-channels-in-secretory-epithelial-cells
#6
Chengtao Yang, Vivian Gonzalez-Perez, Taro Mukaibo, James E Melvin, Xiao-Ming Xia, Christopher J Lingle
Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca(2+)- and voltage-dependent BK-type K(+) channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca(2+), suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KO mice with a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons...
May 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28373283/distinct-domains-of-the-%C3%AE-1-subunit-cytosolic-n-terminus-control-surface-expression-and-functional-properties-of-large-conductance-calcium-activated-potassium-bk-channels
#7
Lie Chen, Danlei Bi, Zen Huat Lu, Heather McClafferty, Michael J Shipston
The properties and function of large-conductance calcium- and voltage-activated potassium (BK) channels are modified by the tissue-specific expression of regulatory β1-subunits. Although the short cytosolic N-terminal domain of the β1-subunit is important for controlling both BK channel trafficking and function, whether the same, or different, regions of the N terminus control these distinct processes remains unknown. Here we demonstrate that the first six N-terminal residues including Lys-3, Lys-4, and Leu-5 are critical for controlling functional regulation, but not trafficking, of BK channels...
May 26, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28202492/gating-ring-strengthens-marriage-of-bk-channel-voltage-sensing-to-pore-opening
#8
Caitlin Sedwick
A new JGP study shows that the gating ring helps the voltage-sensing domain open the BK channel's pore.
March 6, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28196879/deletion-of-cytosolic-gating-ring-decreases-gate-and-voltage-sensor-coupling-in-bk-channels
#9
Guohui Zhang, Yanyan Geng, Yakang Jin, Jingyi Shi, Kelli McFarland, Karl L Magleby, Lawrence Salkoff, Jianmin Cui
Large conductance Ca(2+)-activated K(+) channels (BK channels) gate open in response to both membrane voltage and intracellular Ca(2+) The channel is formed by a central pore-gate domain (PGD), which spans the membrane, plus transmembrane voltage sensors and a cytoplasmic gating ring that acts as a Ca(2+) sensor. How these voltage and Ca(2+) sensors influence the common activation gate, and interact with each other, is unclear. A previous study showed that a BK channel core lacking the entire cytoplasmic gating ring (Core-MT) was devoid of Ca(2+) activation but retained voltage sensitivity (Budelli et al...
March 6, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28195225/a-novel-bk-channel-targeted-peptide-suppresses-sound-evoked-activity-in-the-mouse-inferior-colliculus
#10
L L Scott, E J Brecht, A Philpo, S Iyer, N S Wu, S J Mihic, R W Aldrich, J Pierce, J P Walton
Large conductance calcium-activated (BK) channels are broadly expressed in neurons and muscle where they modulate cellular activity. Decades of research support an interest in pharmaceutical applications for modulating BK channel function. Here we report a novel BK channel-targeted peptide with functional activity in vitro and in vivo. This 9-amino acid peptide, LS3, has a unique action, suppressing channel gating rather than blocking the pore of heterologously expressed human BK channels. With an IC50 in the high picomolar range, the apparent affinity is higher than known high affinity BK channel toxins...
February 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28165042/relationship-between-auxiliary-gamma-subunits-and-mallotoxin-on-bk-channel-modulation
#11
Xin Guan, Qin Li, Jiusheng Yan
The large-conductance, calcium- and voltage-activated K(+)(BK) channel consists of the pore-forming α subunits (BKα) and auxiliary subunits. The auxiliary γ1-3 subunits potently modulate the BK channel by shifting its voltage-dependence of channel activation toward the hyperpolarizing direction by approximately 145 mV (γ1), 100 mV (γ2), and 50 mV (γ3). Mallotoxin is a potent small-molecule BK channel activator. We analyzed the relationship between mallotoxin and the γ subunits in their BK channel-activating effects in membrane patches excised from HEK-293 cells...
February 6, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28090300/bk-channels-in-rat-and-human-pulmonary-smooth-muscle-cells-are-bk%C3%AE-%C3%AE-1-functional-complexes-lacking-the-oxygen-sensitive-stress-axis-regulated-exon-insert
#12
Neil D Detweiler, Li Song, Samantha J McClenahan, Rachel J Versluis, Sujay V Kharade, Richard C Kurten, Sung W Rhee, Nancy J Rusch
A loss of K(+) efflux in pulmonary arterial smooth muscle cells (PASMCs) contributes to abnormal vasoconstriction and PASMC proliferation during pulmonary hypertension (PH). Activation of high-conductance Ca(2+)-activated (BK) channels represents a therapeutic strategy to restore K(+) efflux to the affected PASMCs. However, the properties of BK channels in PASMCs-including sensitivity to BK channel openers (BKCOs)-are poorly defined. The goal of this study was to compare the properties of BK channels between PASMCs of normoxic (N) and chronic hypoxic (CH) rats and then explore key findings in human PASMCs...
December 2016: Pulmonary Circulation
https://www.readbyqxmd.com/read/27807200/molecular-determinants-of-bk-channel-functional-diversity-and-functioning
#13
REVIEW
Ramon Latorre, Karen Castillo, Willy Carrasquel-Ursulaez, Romina V Sepulveda, Fernando Gonzalez-Nilo, Carlos Gonzalez, Osvaldo Alvarez
Large-conductance Ca(2+)- and voltage-activated K(+) (BK) channels play many physiological roles ranging from the maintenance of smooth muscle tone to hearing and neurosecretion. BK channels are tetramers in which the pore-forming α subunit is coded by a single gene (Slowpoke, KCNMA1). In this review, we first highlight the physiological importance of this ubiquitous channel, emphasizing the role that BK channels play in different channelopathies. We next discuss the modular nature of BK channel-forming protein, in which the different modules (the voltage sensor and the Ca(2+) binding sites) communicate with the pore gates allosterically...
2017: Physiological Reviews
https://www.readbyqxmd.com/read/27806944/the-mechanosensitive-bk%C3%AE-%C3%AE-1-channel-localizes-to-cilia-of-principal-cells-in-rabbit-cortical-collecting-duct-ccd
#14
Rolando Carrisoza-Gaytán, Lijun Wang, Carlos Schreck, Thomas R Kleyman, Wen-Hui Wang, Lisa M Satlin
Within the CCD of the distal nephron of the rabbit, the BK (maxi K) channel mediates Ca(2+)- and/or stretch-dependent flow-induced K(+) secretion (FIKS) and contributes to K(+) adaptation in response to dietary K(+) loading. An unresolved question is whether BK channels in intercalated cells (ICs) and/or principal cells (PCs) in the CCD mediate these K(+) secretory processes. In support of a role for ICs in FIKS is the higher density of immunoreactive apical BKα (pore-forming subunit) and functional BK channel activity than detected in PCs, and an increase in IC BKα expression in response to a high-K(+) diet...
January 1, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/27798183/%C3%AE-2%C3%AE-2-controls-the-function-and-trans-synaptic-coupling-of-cav1-3-channels-in-mouse-inner-hair-cells-and-is-essential-for-normal-hearing
#15
Barbara Fell, Stephanie Eckrich, Kerstin Blum, Tobias Eckrich, Dietmar Hecker, Gerald J Obermair, Stefan Münkner, Veit Flockerzi, Bernhard Schick, Jutta Engel
The auxiliary subunit α2δ2 modulates the abundance and function of voltage-gated calcium channels. Here we show that α2δ2 mRNA is expressed in neonatal and mature hair cells. A functional α2δ2-null mouse, the ducky mouse (du), showed elevated auditory brainstem response click and frequency-dependent hearing thresholds. Otoacoustic emissions were not impaired pointing to normal outer hair cell function. Peak Ca(2+) and Ba(2+) currents of mature du/du inner hair cells (IHCs) were reduced by 30-40%, respectively, and gating properties, such as the voltage of half-maximum activation and voltage sensitivity, were altered, indicating that Cav1...
October 26, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27763639/functional-kca1-1-channels-are-crucial-for-regulating-the-proliferation-migration-and-differentiation-of-human-primary-skeletal-myoblasts
#16
Rajeev B Tajhya, Xueyou Hu, Mark R Tanner, Redwan Huq, Natee Kongchan, Joel R Neilson, George G Rodney, Frank T Horrigan, Lubov T Timchenko, Christine Beeton
Myoblasts are mononucleated precursors of myofibers; they persist in mature skeletal muscles for growth and regeneration post injury. During myotonic dystrophy type 1 (DM1), a complex autosomal-dominant neuromuscular disease, the differentiation of skeletal myoblasts into functional myotubes is impaired, resulting in muscle wasting and weakness. The mechanisms leading to this altered differentiation are not fully understood. Here, we demonstrate that the calcium- and voltage-dependent potassium channel, KCa1...
October 20, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27747371/estradiol-modified-prolactin-secretion-independently-of-action-potentials-and-ca-2-and-blockade-of-outward-potassium-currents-in-gh3-cells
#17
Manuel Sánchez, Lorena Suárez, Begoña Cantabrana, Javier Bordallo
Estrogens facilitate prolactin (PRL) secretion acting on pituitary cells. In GH3 cells, estradiol induces acute action potentials and oscillations of intracellular Ca(2+) associated with the secretagogue function. Estradiol modulates several ion channels which may affect the action potential rate and the release of PRL in lactotroph cells, which might depend on its concentration. The aims were to characterize the acute effect of supraphysiological concentrations of estradiol on Ca(2+) and noninactivating K(+) currents and measure the effect on the spontaneous action potentials and PRL release in the somatolactotroph cell line, GH3...
January 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/27690717/the-glycosylation-of-the-extracellular-loop-of-%C3%AE-2-subunits-diversifies-functional-phenotypes-of-bk-channels
#18
Zhi-Gang Huang, Hao-Wen Liu, Zhen-Zhen Yan, Sheng Wang, Lu-Yang Wang, Jiu-Ping Ding
Large-conductance Ca(2+)- and voltage-activated potassium (MaxiK or BK) channels are composed of a pore-forming α subunit (Slo) and 4 types of auxiliary β subunits or just a pore-forming α subunit. Although multiple N-linked glycosylation sites in the extracellular loop of β subunits have been identified, very little is known about how glycosylation influences the structure and function of BK channels. Using a combination of site-directed mutagenesis, western blot and patch-clamp recordings, we demonstrated that 3 sites in the extracellular loop of β2 subunit are N-glycosylated (N-X-T/S at N88, N96 and N119)...
March 4, 2017: Channels
https://www.readbyqxmd.com/read/27298368/closed-state-coupled-c-type-inactivation-in-bk-channels
#19
Jiusheng Yan, Qin Li, Richard W Aldrich
Ion channels regulate ion flow by opening and closing their pore gates. K(+) channels commonly possess two pore gates, one at the intracellular end for fast channel activation/deactivation and the other at the selectivity filter for slow C-type inactivation/recovery. The large-conductance calcium-activated potassium (BK) channel lacks a classic intracellular bundle-crossing activation gate and normally show no C-type inactivation. We hypothesized that the BK channel's activation gate may spatially overlap or coexist with the C-type inactivation gate at or near the selectivity filter...
June 21, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27238265/modulation-of-bk-channels-by-small-endogenous-molecules-and-pharmaceutical-channel-openers
#20
T Hoshi, S H Heinemann
Voltage- and Ca(2+)-activated K(+) channels of big conductance (BK channels) are abundantly found in various organs and their relevance for smooth muscle tone and neuronal signaling is well documented. Dysfunction of BK channels is implicated in an array of human diseases involving many organs including the nervous, pulmonary, cardiovascular, renal, and urinary systems. In humans a single gene (KCNMA1) encodes the pore-forming α subunit (Slo1) of BK channels, but the channel properties are variable because of alternative splicing, tissue- and subcellular-specific auxiliary subunits (β, γ), posttranslational modifications, and a multitude of endogenous signaling molecules directly affecting the channel function...
2016: International Review of Neurobiology
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