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

Abstract

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.