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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
BK (encoded by the KCNMA1 gene) is a ubiquitously expressed K+ channel consisting of four pore-forming α-subunits. The BK channel α-subunit shares homology with all other voltage-sensitive K+ channels containing six transmembrane segments (S1–S6). Uniquely, it has an additional transmembrane segment, S0, and thus the N-terminus is extracellular. Segments S1-S4 form the VSD, and the pore region is located between S5 and S6. The cytoplasmic C-terminal domain of BK channel encompasses two domains termed Regulators of Conductance for K+ (RCK): the proximal RCK1 and the distal RCK2. Each RCK contains a high affinity Ca²⁺-binding site. Compared with other K+ channels, it is characterized by a large K+ conductance with dual activation by membrane depolarization and elevated cytosolic Ca2+ (Berkefeld et al., 2006; Fakler and Adelman, 2008; Salkoff et al., 2006) (Figure 18.6A).
Cholesterol Modulation of BK (MaxiK; Slo1) Channels
Published in Qiu-Xing Jiang, New Techniques for Studying Biomembranes, 2020
Alex M. Dopico, Anna N. Bukiya, Kelsey North
BK channels are widely expressed in mammalian tissues. In most tissues, BK channels are heteromeric complexes (Figure 7.1) resulting from the association of four BK channel-forming subunits (α), which are encoded by the KCNMA1 or Slo1 gene (these homo-tetramers are often refer to as slo1 channels) and small, regulatory subunits (β1–β4), which are encoded by KCNMB1-4 genes. Slo1 pre-mRNA undergoes abundant alternative splicing, editing and further regulation by miRNA (Shipston and Tian, 2016). These processes, followed by posttranslational modification of both α (Kyle and Braun, 2014; Shipston and Tian, 2016) and β subunits (Lu et al., 2006; Li and Yan, 2016) primarily determine the BK current phenotype. BK channel γ subunits (i.e., leucine-rich repeat containing, or LRRC proteins) have also been identified, and drastically modify BK currents (Lu et al., 2006; Evanson et al., 2014; Li and Yan, 2016) yet the physiological significance of γ subunits in most tissues remains to be fully established.
Pathophysiology of neurogenic detrusor overactivity
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Alexandra McPencow, Toby C. Chai
The large conductance of calcium-activated potassium channel (BK) has been shown to be important regulator of normal human and mouse DSM contractility.44,45 When BK is open (activated by increased intracellular calcium and/or cellular depolarization), potassium flows out of the cell, thus hyperpolarizing the cell and reducing the ability of the cell to contract and/or generate spontaneous activity. The depiction of BK morphology is shown in Figure 7.5. Each BK channel is composed of 4 units (tetramer) of BK protein. Each BK protein unit has an α-subunit (pore-forming unit) and a β-subunit (regulatory unit). Each α-subunit has seven transmembrane domains, whereas each β-subunit has two transmembrane domains. Alternative splicing of the BK gene (KCNMA1) can further regulate the properties of the BK channel.
Why do platelets express K+ channels?
Published in Platelets, 2021
Joy R Wright, Martyn P. Mahaut-Smith
KCa 1.1, encoded by the gene KCNMA1, is a large conductance calcium-activated K+ channel also known as BK, Maxi-K and Slo1. The functional channel is formed by a tetrameric assembly of alpha subunits, which can be associated with beta subunits that modify its function [63]. The opening of the channel is stimulated (gated) independently and synergistically by an increase in cytosolic Ca2+ and membrane depolarization. A very recent study has detected KCa1.1 using antibody-based techniques in human platelets and megakaryocytes [16]. Agonists (openers) of the channel exert an inhibitory effect on several functional responses, including aggregation or adhesion of platelets and proplatelet formation or cell spreading in megakaryocytes. The openers induce membrane hyperpolarization, as expected for an increase in relative permeability to K+. These results agree with an earlier study in which epoxyeicosatrienoic acids known to be released from endothelial cells induced a membrane hyperpolarization of human platelets that was blocked by iberiotoxin, a relatively selective KCa1.1 inhibitor [64]. Pharmacological openers of KCa1.1 also reduced the cytosolic Ca2+ responses to ADP [16]. At present, it is unclear why the membrane depolarization observed with the block of Kv1.3 [6] (see earlier section) and hyperpolarisation following KCa1.1 activation both lead to a reduced agonist-evoked Ca2+ response. The role of membrane potential per se in platelet and megakaryocyte function clearly merits further study. Electrophysiological measurements of KCa1.1 channels in platelets or megakaryocytes are also awaited and may require studies in human samples as patch clamp of Kv1.3-deficient megakaryocytes failed to detect other voltage-gated K+ conductances; thus, there may be a species difference [6].