TALK-1 channels control β cell endoplasmic reticulum Ca 2+ homeostasis.

Autor:	Vierra NC; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Dadi PK; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Milian SC; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Dickerson MT; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Jordan KL; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA., Gilon P; Pôle d'endocrinologie, diabète et nutrition, Institut de recherche expérimentale et clinique, Université catholique de Louvain, Brussels 1200, Belgium., Jacobson DA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. david.a.jacobson@vanderbilt.edu.
Jazyk:	angličtina
Zdroj:	Science signaling [Sci Signal] 2017 Sep 19; Vol. 10 (497). Date of Electronic Publication: 2017 Sep 19.
DOI:	10.1126/scisignal.aan2883
Abstrakt:	Ca ²⁺ handling by the endoplasmic reticulum (ER) serves critical roles in controlling pancreatic β cell function and becomes perturbed during the pathogenesis of diabetes. ER Ca ²⁺ homeostasis is determined by ion movements across the ER membrane, including K ⁺ flux through K ⁺ channels. We demonstrated that K ⁺ flux through ER-localized TALK-1 channels facilitated Ca ²⁺ release from the ER in mouse and human β cells. We found that β cells from mice lacking TALK-1 exhibited reduced basal cytosolic Ca ²⁺ and increased ER Ca ²⁺ concentrations, suggesting reduced ER Ca ²⁺ leak. These changes in Ca ²⁺ homeostasis were presumably due to TALK-1-mediated ER K ⁺ flux, because we recorded K ⁺ currents mediated by functional TALK-1 channels on the nuclear membrane, which is continuous with the ER. Moreover, overexpression of K ⁺ -impermeable TALK-1 channels in HEK293 cells did not reduce ER Ca ²⁺ stores. Reduced ER Ca ²⁺ content in β cells is associated with ER stress and islet dysfunction in diabetes, and islets from TALK-1-deficient mice fed a high-fat diet showed reduced signs of ER stress, suggesting that TALK-1 activity exacerbated ER stress. Our data establish TALK-1 channels as key regulators of β cell ER Ca ²⁺ and suggest that TALK-1 may be a therapeutic target to reduce ER Ca ²⁺ handling defects in β cells during the pathogenesis of diabetes. (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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