**1. Introduction**

In cochlea, the BK channels are localized in both presynaptic and extrasynaptic zone near the apical portion of inner hair cells (IHC) and outer hair cells (OHC). The BK channels are

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

known to be involved in noise-induced hearing loss (NIHL) [1] through activation of Ca2+ induced Ca2+ release and ROS pathway by association of BKAPs like SOD, peroxidase, catalase and GSTμ, [2]. In addition, BK channel is known to be associated with deafness proteins like γ-actin and methylthioadenosine phosphorylase (MTAP) [3]. The molecular mechanisms that regulate the BK channel and their role in NIHL and deafness remain unclear. Therefore, understanding mechanisms of BK channel regulation and its associated proteins (BKAPs) will provide insights in understanding the problems in deafness and NIHL.

Mitochondria-associated ER membranes (MAMs) control Ca2+ influx between ER and mitochondria. We found that BKα subunits [2] are localized in the inner mitochondrial membrane and interacted directly with other BKAPs like, IP3R1, calreticulin at the ER face of the MAMs, and the molecular chaperone grp78, which bridges the IP3R-1 with voltage-dependent anion channel (VDAC-1) of the outer mitochondrial membrane (OMM) [4]. The BK channel is associated with all other proteins having a contribution in mitochondria-associated ER membranes. Therefore, the functional regulation of BK channel and its role in MAMs remains unclear.

The novel concept of mechanism of apoptosis is in addition to molecular genes, ionic homeostasis also induces apoptosis especially K+ in cell [5]. The ionic mechanism of apoptosis associates the accumulation of intracellular Ca2+ leading to uncontrolled K+ efflux resulting in the early steps in apoptosis [6]. The BK channels play a critical role in mediating the K+ efflux linked with apoptotic cell shrinkage. Inhibition of BK channel with iberiotoxin dramatically reduced K+ efflux and prevents apoptosis. Therefore, enhanced K<sup>+</sup> efflux is an essential mediator not only for early apoptotic cell shrinkage but also for downstream of caspase-3 activation and DNA fragmentation.

and activate cytosolic domain. The cytosolic domains are connected with transmembrane spanning region, S6 by 17 amino acid peptide chain, called linker peptide. A cytosolic domain through linker peptide opens and activates the gate PGD domain. Recently the cryo-EM study

The Role of Calcium-activated Potassium Channel in Mitochondria-Associated ER Membrane…

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The leucine zipper (LZ) motif is originally described as DNA binding proteins and reported to play an important role in both assemblies of ion channels and interactions of protein kinase and protein phosphatase. The LZ motifs serve to anchor a number of different BK channel associated proteins [10]. The LZ and EF-hand motif containing proteins regulate the mitochondrial swelling leading to apoptosis [11]. Therefore, it can be concluded that BK and other interacting proteins are regulating apoptosis through post-translational modification of phos-

BKα channels are sensitive to Ca2+ regulation through phosphorylation by serine-threonine and tyrosine kinases [12, 13]. Thirty putative phosphorylation sites were identified from seven different BKα splice variants [8]. Among them, the BK-DEC variant has an additional 60 amino acids at the extreme end of the C-terminus which contains 11 serine/threonine and tyrosine residues. The BK channels are directly involved in tyrosine phosphorylation in the presence of c-Src kinase domain in C-terminus of channel. The vital role for c-Src kinase mediating signal transduction on G-protein coupled and integrin receptor activation leads to the regulation of membrane ion channels [12]. The α5β1 integrin activation leads to increasing activity of BK channel. The BK channel phosphorylation of α5β1 integrin at Tyr-766 through

The PKC phosphorylation site (S1076) is lying on c-terminus of human BKα channel that influences the regulation of protein kinase on BKα channel activity which may subsequently alter pulmonary smooth muscle tone functions [15, 16]. This reveals the dual role of PKC on BK channel on tracheal smooth muscle. They are phosphorylation of S695 by PKC on BK

illustrates the BK channel structure and gating pore size is 1.7–2.0 ηm resolution [9].

phorylation or palmitoylation (**Figure 1**) [10].

**Figure 1.** Significant phosphorylation sites in BKα subunit.

intracellular signaling pathway involving c-Src kinase [14].
