Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P(3) and IP(3)-receptors

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Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P(3) and IP(3)-receptors

author Wong, A
author Grubb, DR
author Cooley, N
author Luo, J
author Woodcock, EA
Year 2013
citation J Mol Cell Cardiol 2013;54:19-24
issn 0022-2828
URI http://hdl.handle.net/11187/1526
abstract Autophagy is a process that removes damaged proteins and organelles and is of particular importance in terminally differentiated cells such as cardiomyocytes, where it has primarily a protective role. We investigated the involvement of inositol(1,4,5)trisphosphate (Ins(1,4,5)P(3)) and its receptors in autophagic responses in neonatal rat ventricular myocytes (NRVM). Treatment with the IP(3)-receptor (IP(3)-R) antagonist 2-aminoethoxydiphenyl borate (2-APB) at 5 or 20 μmol/L resulted in an increase in autophagosome content, defined as puncta labeled by antibody to microtubule associated light chain 3 (LC3). 2-APB also increased autophagic flux, indicated by heightened LC3II accumulation, which was further enhanced by bafilomycin (10nmol/L). Expression of Ins(1,4,5)P(3) 5-phosphatase (IP(3)-5-Pase) to deplete Ins(1,4,5)P(3) also increased LC3-labeled puncta and LC3II content, suggesting that Ins(1,4,5)P(3) inhibits autophagy. The IP(3)-R can act as an inhibitory scaffold sequestering the autophagic effector, beclin-1 to its ligand binding domain (LBD). Expression of GFP-IP(3)-R-LBD inhibited autophagic signaling and furthermore, beclin-1 co-immunoprecipitated with the IP(3)-R-LBD. A mutant GFP-IP(3)-R-LBD with reduced ability to bind Ins(1,4,5)P(3) bound beclin-1 and inhibited autophagy similarly to the wild type sequence. These data provide evidence that Ins(1,4,5)P(3) and IP(3)-R act as inhibitors of autophagic responses in cardiomyocytes. By suppressing autophagy, IP(3)-R may contribute to cardiac pathology. Copyright © 2012 Elsevier Ltd. All rights reserved.
sponsorship NHMRC: 526621, 526623, 586621 Other
publisher Elsevier
title Regulation of autophagy in cardiomyocytes by Ins(1,4,5)P(3) and IP(3)-receptors
type Journal Article
doi 10.1016/j.yjmcc.2012.10.014


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