Year: 2015
Type: article
Abstract: The type 2 ryanodine receptor (RyR2) is a Ca2+ release channel on the endoplasmic reticulum (ER) of several types of cells, including cardiomyocytes and pancreatic β cells. In cardiomyocytes, RyR2-dependent Ca2+ release is critical for excitation-contraction coupling; however, a functional role for RyR2 in β cell insulin secretion and diabetes mellitus remains controversial. Here, we took advantage of rare RyR2 mutations that were identified in patients with a genetic form of exercise-induced sudden death (catecholaminergic polymorphic ventricular tachycardia [CPVT]). As these mutations result in a "leaky" RyR2 channel, we exploited them to assess RyR2 channel function in β cell dynamics. We discovered that CPVT patients with mutant leaky RyR2 present with glucose intolerance, which was heretofore unappreciated. In mice, transgenic expression of CPVT-associated RyR2 resulted in impaired glucose homeostasis, and an in-depth evaluation of pancreatic islets and β cells from these animals revealed intracellular Ca2+ leak via oxidized and nitrosylated RyR2 channels, activated ER stress response, mitochondrial dysfunction, and decreased fuel-stimulated insulin release. Additionally, we verified the effects of the pharmacological inhibition of intracellular Ca2+ leak in CPVT-associated RyR2-expressing mice, in human islets from diabetic patients, and in an established murine model of type 2 diabetes mellitus. Taken together, our data indicate that RyR2 channels play a crucial role in the regulation of insulin secretion and glucose homeostasis.
DOI: 10.1172/jci79273
Institutions: Columbia University Irving Medical Center, Columbia University, University of Molise, Imperial College London, University of Naples Federico II, Università Cattolica del Sacro Cuore, Leiden University, University of Campania "Luigi Vanvitelli", Leiden University Medical Center, University of Parma, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Indiana University Bloomington, Indiana University Indianapolis, Indiana University School of Medicine, Centre National de la Recherche Scientifique
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G158742588, G2849293528, Cardiac and skeletal muscle calcium release channels, Intracellular calcium leak and muscle function, Novel Therapeutic Approaches to Atrial Fibrillation Targeting Intracellular Calci, Regulation of cardiac ion channel function via allosteric modulators, G8296181329, G9000200827, Indiana Diabetes Research Center
OpenAlex ID: W2006446390