**7. Conclusions**

through induces Bid translocation to mitochondria [38]. The first direct ER-mitochondrial tethering proteins are Mfn1 and Mfn2 [39]. They are localized on both organelles membrane and close contact point between the organelles. In addition, they are involved in maintaining the shape of both organelles. Moreover the regular juxtaposition of ER and mitochondria is the cytoskeletal network [40]. Both the organelles were bound with microtubules (MTs) and actin cytoskeleton that provide a scaffold that stabilizes the contact points between the compartments [41]. Recently identified mitostatin protein is binds with keratin and intermediate

**6. The role of bk channel role in mitochondria and ER interactions**

Earlier, the molecular mechanism of BK channel function in mouse cochlea we studied, through the system biology approach aided by the sensitivity of coimmunoprecipitation, shotgun mass spectrometry methods to identify 174 BK channel associated proteins (BKAPs). Based on BKAPs developed transient BKα interaction networks are enriched with functional attributes of metabolism, trafficking and scaffolding, development and differentiation, signal transduction, and transport [2]. We, for the first time, employed a large number of ion channel associating proteins in the cochlea. The BKAPs were analyzed through subcellular localization. The majority of the BKAPs nearly 30 and 15% were localized in mitochondria (both membrane and matrix) and endoplasmic reticulum. Comprehensive understanding of the BK channel role in mitochondria and endoplasmic reticulum function has remained unclear. The past decade has concealed an number of unexpected proteinprotein interactions that fundamentally changed our view of the localization and functional interactions of proteins inside cells. The functional role of BK channel in mitochondria is

One of our recent bioinformatics studies has revealed that the proteomics data (BKAPs) with functional attributes remarkably identified nearly 20 and 10% of novel mitochondrial and endoplasmic reticulum BKAPs involved in pro-apoptotic and anti-apoptotic properties which have not been looked in to, so far. Based on these results the preliminary experiments of tunnel assay for the BK overexpressed CHO cells that confirmed 65% cell death when compared with control. Till now, the exact mechanism behind the mitoBK and ER-BK channel role in pro-apoptosis is not known. It is expected that proposed project will give a new dimension in the biomedical field, which in turn may be useful for understanding the mechanism of hear-

The Ca2+ activated potassium channel is playing a predominant role in mitochondria and endoplasmic reticulum-associated proteins. These proteins were contributing either K<sup>+</sup>

[2]. Superoxide dismutase, glutathione S transferase μ, GAPDH, VDAC, and peroxidase are involved in ROS pathway as well as the candidate for BK channel associated proteins. The endoplasmic reticulum proteins calreticulin, GRP78, inositol triphosphate receptor (InsP3R), protein SET, VCP, HSP70, and protein disulfide isomerase are involved in the regulation of calcium-induced calcium release (CICR), protein folding and clearance. These proteins are known to BK channel associated proteins [2]. These two groups of proteins are involved in

efflux of cells through the Ca2+ ion binds with Ca2+ bowl of c-terminus region

filaments that inhibits the juxtaposition of ER and mitochondria.

62 Current Understanding of Apoptosis - Programmed Cell Death

no exception.

influx or K<sup>+</sup>

ing loss and noise-induced hearing loss (NIHL).

BK channel is involved in the regulation of pro-apoptosis in mouse cochlear hair cells. A group of proteins is involved in the regulation of mitochondria-associated ER membrane (MAMs) and in the maintenance of intracellular Ca2+ level in cells. The MAMs associated proteins are known to be BK channel associated proteins. However, the details of interactions of MAMS associated proteins with BK channel and their mechanisms of post-translational modification such as phosphorylation and palmitoylation remain elusive. It is proposed that the present study will clearly depict how BKα is involved in apoptosis through K<sup>+</sup> efflux and regulation of BKAPs by phosphorylation. The phosphorylation of activation or inactivation of specific kinases and phosphatase binding motifs mainly regulate the channel gating and different signaling pathways. From these studies, we gain the knowledge of the mechanism of BK channel mediated apoptosis and identification of novel therapeutics to inhibit intracellular calcium induced stress-related apoptosis in cochlear hair cells. Therefore, through this study it is expected to find novel therapeutics for deafness and noise-induced hearing loss population in our society.

[3] Williamson RE, Darrow KN, Michaud S, Jacobs JS, Jones MC, Eberl DF, Maas RL, Liberman MC, Morton CC. Methylthioadenosine phosphorylase (MTAP) in hearing: Gene disruption by chromosomal rearrangement in a hearing impaired individual and model organism analysis. American Journal of Medical Genetics. Part A. 2007 Jul 15;

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

http://dx.doi.org/10.5772/intechopen.77329

65

[4] de Brito OM, Scorrano L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria.

[5] Franco R, DeHaven WI, Sifre MI, Bortner CD, Cidlowski JA. Glutathione depletion and disruption of intracellular ionic homeostasis regulate lymphoid cell apoptosis. Journal

[6] Roy DN, Mandal S, Sen G, Mukhopadhyay S, Biswas T. 14-Deoxyandrographolide desensitizes hepatocytes to tumour necrosis factor-alpha-induced apoptosis through calcium-dependent tumour necrosis factor receptor superfamily member 1A release via the NO/cGMP pathway. British Journal of Pharmacology. 2010 Aug 1;**160**(7):1823-1843 [7] Salkoff L, Butler A, Ferreira G, Santi C, Wei A. High-conductance potassium channels of

[8] Yan J, Olsen JV, Park KS, Li W, Bildl W, Schulte U, Aldrich RW, Fakler B, Trimmer JS. Profiling the phospho-status of the BKCa channel α subunit in rat brain reveals unexpected patterns and complexity. Molecular & Cellular Proteomics. 2008 Nov 1;**7**(11):

[9] Yuan P, Leonetti MD, Pico AR, Hsiung Y, MacKinnon R. Structure of the human BK channel Ca2+-activation apparatus at 3.0 Å resolution. Science. 2010 Jul 9;**329**(5988):182-186 [10] Tian L, Coghill LS, MacDonald SH, Armstrong DL, Shipston MJ. Leucine zipper domain targets cAMP-dependent protein kinase to mammalian BK channels. Journal of

[11] Piao L, Li Y, Kim SJ, Sohn KC, Yang KJ, Park KA, Byun HS, Won M, Hong J, Hur GM, Seok JH. Regulation of OPA1-mediated mitochondrial fusion by leucine zipper/EF-handcontaining transmembrane protein-1 plays a role in apoptosis. Cellular Signalling. 2009

[12] Ling S, Sheng JZ, Braun AP. The calcium-dependent activity of large-conductance, cal-

[13] Zhou XB, Wulfsen I, Utku E, Sausbier U, Sausbier M, Wieland T, Ruth P, Korth M. Dual role of protein kinase C on BK channel regulation. Proceedings of the National Academy

[14] Yang Y, Wu X, Gui P, Wu J, Sheng JZ, Ling S, Braun AP, Davis GE. Davis MJ. α5β1

Ca2+ sensitivity through c-src-mediated channel phosphorylation. Journal of Biological

integrin engagement increases large conductance, Ca2+-activated K+

lation. American Journal of Physiology - Cellular Physiology. 2004 Sep;**287**(3):C698-C706

channels is enhanced by Pyk2-and Hck-induced tyrosine phosphory-

channel current and

the SLO family. Nature Reviews. Neuroscience. 2006 Dec 1;**7**(12):921-931

**143**(14):1630-1639

2188-2198

May 31;**21**(5):767-777

cium-activated K+

Nature. 2008 Dec 4;**456**(7222):605-610

of Biological Chemistry. 2008 Dec 26;**283**(52):36071-36087

Biological Chemistry. 2003 Mar 7;**278**(10):8669-8677

of Sciences. 2010 Apr 27;**107**(17):8005-8010

Chemistry. 2010 Jan 1;**285**(1):131-141
