Long-term inhibition of protein tyrosine kinase impairs electrophysiologic activity and a rapid component of exocytosis in pancreatic beta cells

Zhao, Yu-Feng, Keating, Damien J, Hernandez, Maria, Feng, Dan Dan, Zhu, Yulong and Chen, Chen (2005) Long-term inhibition of protein tyrosine kinase impairs electrophysiologic activity and a rapid component of exocytosis in pancreatic beta cells. Journal of Molecular Endocrinology, 35 1: 49-59. doi:10.1677/jme.1.01779

Author Zhao, Yu-Feng
Keating, Damien J
Hernandez, Maria
Feng, Dan Dan
Zhu, Yulong
Chen, Chen
Title Long-term inhibition of protein tyrosine kinase impairs electrophysiologic activity and a rapid component of exocytosis in pancreatic beta cells
Journal name Journal of Molecular Endocrinology   Check publisher's open access policy
ISSN 1479-6813
Publication date 2005
Year available 2005
Sub-type Article (original research)
DOI 10.1677/jme.1.01779
Volume 35
Issue 1
Start page 49
End page 59
Total pages 11
Place of publication Bristol, England
Publisher Society for Endocrinology
Collection year 2005
Language eng
Subject 110306 Endocrinology
110201 Cardiology (incl. Cardiovascular Diseases)
111201 Cancer Cell Biology
Abstract Dysfunction of pancreatic -cells is a fundamental feature in the pathogenesis of type 2 diabetes. As insulin receptor signaling occurs via protein tyrosine kinase (PTK), we investigated the role of PTK activity in the etiology of -cell dysfunction by inhibiting PTK activity in primary cultured mouse pancreatic -cells and INS-1 cells with genistein treatment over 24 h. Electrophysiologic recordings showed genistein treatment significantly attenuated ATP-sensitive K+ (KATP) and voltage-dependent Ca2+ currents, and depolarized the resting membrane potential in primary -cells. When stimulated by high glucose, genistein-treated -cells exhibited a time delay of both depolarization and Ca2+ influx, and were unable to fire action potentials, as well as displaying a reduced level of Ca2+ influx and a loss of Ca2+ oscillations. Semiquantitative PCR analysis revealed decreased expression of KATP and L-type Ca2+ channel mRNA in genistein-treated islets. PTK inhibition also significantly reduced the rapid component of secretory vesicle exocytosis, as indicated by membrane capacitance measurements, and this is likely to be due to the reduced Ca2+ current amplitude in these cells. These results illustrate that compromised PTK activity contributes to pancreatic -cell dysfunction and may be involved in the etiology of type 2 diabetes.
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