1.A.1.3.2
Large conductance or L-type Ca²⁺ and voltage-activated K⁺ channel (LTCC), α-subunit (subunit α1), BK, BK_Ca, Kca1.1, Slowpoke, Slo1, KCNMA1 or MaxiK (functions with four β-subunits (TC# 8.A.14) encoded by genes KCNMB1-4 and the γ subunit (TC# 8.A.43) in humans (Toro et al. 2013; Li et al. 2016); the positions of beta2 and beta3 have been determined (Wu et al. 2013).  The KB channel is inhibited by 3 scorpion toxins, charybda toxin, iberiotoxin and slotoxin.  It forms a ''Ca²⁺  nanodomain'' complex with Cav1.2 (L-type; 1.A.1.11.4), Cav2.1 (P/Q-type; 1.A.1.11.5) and Cav2.2 (N-type; 1.A.1.11.6) where Ca²⁺ influx through the Cav channel activates BK_Ca (Berkefeld et al., 2006; Romanenko et al., 2006). The RCK2 domain is a Ca²⁺ sensor (Yusifov et al., 2008). Binding of Ca²⁺ to D367 and E535 changes the conformation around the binding site and turns the side chain of M513 into a hydrophobic core, explaining how Ca²⁺ binding opens the activation gate of the channel (Zhang et al., 2010). A structural motif in the C-terminal tail of Slo1 confers carbon monoxide sensitivity to human BK_Ca channels (Williams et al., 2008; Hou et al., 2008). These channels are present in the inner mitochondrial membrane of rat brain (Douglas et al., 2006).The Stress-Axis Regulated Exon (STREX) is responsible for stretch sensitivity. Ca²⁺ binds to two sites. Ca²⁺ binding to the RCK1 site is voltage dependent, but Ca²⁺ binding to the Ca²⁺ bowl is not (Sweet and Cox et al., 2008). Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells (Zhao et al., 2010). The open structure is known (Yuan et al., 2012). BK_Ca is essential for ER calcium uptake in neurons and cardiomyocytes (Kuum et al., 2012) and link Ca²⁺ signaling to action potential firing and neurotransmitter release via serotonin receptors in many types of neurons (Rothberg 2012). The molecular mechanism of pharmacological activation of BK channels has been discussed by Gessner et al. (2012). The first TMS of the β2-subunit binds to TMS S1 of the α-subunit (Morera et al., 2012).  Mutations in Cav1.2 give rise to Timothy syndrome (Dixon et al. 2012).  Exhibits low voltage activation by interaction with Cav3 (Rehak et al. 2013) as well as Ca²⁺-gating (Berkefeld and Fakler 2013). Single-channel kinetics have been reported (Geng and Magleby 2014). The γ-subunit has TC# 8.A.43.1.8.  RBK channels regulate myogenesis in vascular smooth muscle cells (Krishnamoorthy-Natarajan and Koide 2016). Latorre et al. 2017 reviewed molecular, physiological and pathological aspects of Slo1. The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017), thereby reducing pain. The N-terminal sequence determines its modification by β-subunits (Lorca et al. 2017). Inhibition of BKCa negatively alters cardiovascular function (Patel et al. 2018). BKCa may be the target of verteporfin, a benzoporphyrin photosensitizer that alters membrane ionic currents (Huang et al. 2019). Globotriaosylceramide (Gb3) accumulates due to mutations in the gene encoding alpha-galactosidase A. Gb3 deposition in skin fibroblasts impairs KCa1.1 activity and activate the Notch1 signaling pathway, resulting in an increase in pro-inflammatory mediator expression, and thus, contributing to cutaneous nociceptor sensitization as a potential mechanism of FD-associated pain (Rickert et al. 2019). This channel may be present in mitochondria (Parrasia et al. 2019). The Slo3 (TC# 1.A.1.3.5) cytosolic module confers pH-dependent regulation whereas the Slo1 cytosolic module confers Ca²⁺-dependent regulation (Xia et al. 2004). Elevated extracellular Ca²⁺ aggravates iron-induced neurotoxicity because LTCCs mediate iron transport in dopaminergic neurons and this, in turn, results in elevated intracellular Ca²⁺ and further aggravates iron-induced neurotoxicity (Xu et al. 2020). Agonists include BMS-191011, NS1619, NS11021, epoxyeicosatrienoic acid isoforms, while inhibitors include iberiotoxin and penitrem A which have been used to study the system in megakaryocytes and platelets (Balduini et al. 2021). Medicinal plant products can interact with BKCa (Rajabian et al. 2022).  A potent and selective activator of large-conductance Ca²⁺-activated K⁺ channels induces preservation of mitochondrial function after hypoxia and reoxygenation by handling of calcium and transmembrane potential (de Souza et al. 2024). Neither the closed channel conformation obtained in the absence of Ca²⁺ nor an intermediate conformation found in the presence of Ca²⁺ show density for the N-terminus of the β2 subunit in their pore, likely due to narrower side access portals preventing their entry into the channel pore. Thus, a ball-and-chain inactivation mechanism is proposed (Agarwal et al. 2025).