Regulation of the type III inositol 1,4,5-trisphosphate receptor

Authors

Robert Eliot Hagar, University of Connecticut

Date of Completion

January 2002

Keywords

Biology, Cell|Biophysics, Medical

Degree

Ph.D.

Abstract

The inositol 1,4,5-trisphosphate receptor (InsP₃R) is an important intracellular calcium (Ca²⁺) release channel in a variety of tissues. InsP₃-mediated Ca²⁺ release regulates many cellular processes such as muscle contraction, transcription, and long term depression. Three isoforms have been identified, but only the functional properties of the types I and II InsP₃R have been determined. This dissertation examines the regulation of the type III InsP₃R and the physiological role of the type III InsP₃R in an intact cell. A rat insulinoma cell line, RIN-m5F, was used as a source for the type III InsP₃R since these cells preferentially express this isoform. Chapter 1 provides a brief description of normal pancreatic β cells and RIN-m5F cells as well as the clinical consequences of altered insulin secretion. In chapter 2, regulation of the type III InsP₃R by Ca²⁺ is explored. An important functional difference is presented: the type III InsP ₃R is not inhibited by high cytoplasmic Ca²⁺ like the type I InsP₃R. Regulation of the type III InsP₃R by InsP₃ and ATP is described in chapter 3. The type III InsP ₃R requires higher InsP₃ concentrations to reach maximal activity relative to the type I InsP₃R. This result is consistent with the relative order of InsP₃ affinity for the three InsP ₃R isoforms. ATP, an important component of excitation-secretion coupling in the β cell, regulates the type III InsP₃R in a manner which is very similar to the type I InsP₃R. In chapter 4, the nature of Ca²⁺ signaling in RIN-m5F cells is explored. The type III InsP₃R lacks Ca²⁺-dependent inhibition, and this property makes the type III InsP₃R ideal for signal initiation. Activation of the type III InsP₃R results in a single transient, but global, increase in the cytosolic Ca²⁺ concentration. ^

Recommended Citation

Hagar, Robert Eliot, "Regulation of the type III inositol 1,4,5-trisphosphate receptor" (2002). Doctoral Dissertations. AAI3054239.
https://digitalcommons.lib.uconn.edu/dissertations/AAI3054239