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Title page for ETD etd-08072017-135702


Type of Document Dissertation
Author Vierra, Nicholas Catin
URN etd-08072017-135702
Title Insights into TALK-1 Channel Modulation of Islet Cell Calcium Homeostasis and Hormone Secretion
Degree PhD
Department Molecular Physiology and Biophysics
Advisory Committee
Advisor Name Title
Richard O'Brien Committee Chair
Eric Delpire Committee Member
Jerod Denton Committee Member
Roger Colbran Committee Member
Keywords
  • ion channel
  • glucagon
  • somatostatin
  • K2P
  • insulin
  • KCNK16
  • two-pore domain
Date of Defense 2017-07-18
Availability restricted
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 Kslow, a Ca2+-dependent K+ current which repolarizes the plasma membrane potential, terminating each Ca2+ oscillation. Kslow 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.
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