Insights into TALK-1 Channel Modulation of Islet Cell Calcium Homeostasis and Hormone Secretion

Description

The two-pore domain K⁺ (K2P) channel TALK-1 is highly expressed in the pancreatic islet and is linked to type 2 diabetes mellitus (T2DM) risk through a non-synonymous polymorphism (rs1535500). Here, we established that TALK-1 channels are functionally expressed in mouse and human β-cells where they modulate insulin secretion by limiting electrical excitability and cytosolic Ca²⁺ influx. We found that the rs1535500 polymorphism (encoding TALK-1 A277E) increases TALK-1 channel activity. When placed on a high-fat diet, mice lacking TALK-1 channels were protected from elevations in fasting glycemia. Therefore, rs1535500 may contribute to T2DM etiology by exacerbating hyperglycemia under diabetogenic conditions. We next determined that endoplasmic reticulum (ER)-localized TALK-1 channels conduct ER K⁺ countercurrents, facilitating β-cell and δ-cell ER Ca²⁺ leak. In β-cells, TALK-1 regulation of ER Ca²⁺ handling influences activation of K_slow, a Ca²⁺-dependent K⁺ current which repolarizes the plasma membrane potential, terminating each Ca²⁺ oscillation. K_slow is significantly reduced in KO β-cells, contributing to an elevated frequency of Ca²⁺ oscillations in TALK-1 KO islets. Furthermore, we determined that islets from mice lacking TALK-1 channels were resistant to ER stress induced by chronic exposure to a high-fat diet. Finally, we showed that TALK-1 channel regulation of δ-cell ER Ca²⁺ handling impacts δ-cell function. Somatostatin secretion is amplified by Ca²⁺-induced Ca²⁺ release (CICR) from the ER, and we found that TALK-1 regulates δ-cell Ca²⁺ handling and somatostatin secretion by modulating the ER Ca²⁺ stores which underlie CICR. Our data establish TALK-1 channels as key determinants of islet cell Ca²⁺ handling, and suggest that TALK-1 channels may be a therapeutic target to reduce islet cell ER Ca²⁺ defects during the pathogenesis of diabetes.

Links & Downloads

1. http://etd.library.vanderbilt.edu/available/etd-08072017-135702/

Tags

Molecular Physiology and Biophysics

Additional Fields

Identifer	oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-08072017-135702
Date	09 August 2017
Creators	Vierra, Nicholas Catin
Contributors	Jerod Denton, Eric Delpire, Roger Colbran, Richard O'Brien
Publisher	VANDERBILT
Source Sets	Vanderbilt University Theses
Language	English
Detected Language	English
Type	text
Format	application/pdf
Source	http://etd.library.vanderbilt.edu/available/etd-08072017-135702/
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