UNFOLDED PROTEIN RESPONSE IS ACTIVATED IN HEART OF CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR TACHYCARDIA (CPVT) MICE

Rigers Bakiu

doi:10.5937/sjecr15-6707

Rigers Bakiu Agricultural University of Tirana

DOI: https://doi.org/10.5937/sjecr15-6707

Abstract

ABSTRACT

Isoform 2 of calsequestrin (CSQ2), is the main calcium-binding protein of sarcoplasmic reticulum (SR), expressed both in cardiac and in skeletal muscles. CSQ2 acts as an SR calcium (Ca²⁺) sensor and regulates SR Ca²⁺ release via interactions with triadin, junctin, and the ryanodine receptor. Various mutations of the csq2 gene lead to altered Ca²⁺ release and contractile dysfunction contributing to the development of arrhythmias and sudden cardiac death in young individuals affected by CPVT. Transgenic mice carrying one of the identified CSQ2 point-mutations (R33Q) associated to CPVT were developed and a drastic reduction of the mutated protein was observed. Following a biomolecular approach several analysis were performed using different antibody treatments in order to identify when the reduction of CSQ2 begins, unveil the mechanism involved in the reduction of CSQ2 and verify if other proteins are affected by the presence of the mutated protein. This study results showed that mutated CSQ2 decreased soon after birth in conjunction with the decreased levels of other important proteins of the junctional SR, such as triadin (TD). Up-regulation of proteins associated to the unfolded protein response (UPR) was also observed and the pathway activated by UPR was the ATF6-dependent one. The R33Q mutation induced the decrease of CSQ2 by activation of the UPR and subsequently degradation through proteasome.

Keywords: Calsequestrin, CPVT, ERAD, UPR, Triadin, Chaperones.

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