HORMONAL CALCIUM MOBILIZATION--REGULATION IN LIVER

Project Details

Description

The objective of this study is to characterize the second
messenger system which mediates the actions of calcium-
dependent hormones in liver cells. These hormones, which include
epinephrine and vasopressin, stimulate the breakdown of inositol
lipids in the plasma membrane with a resultant release of two
second messengers; diacylglycerol which activates protein kinase
C and inositol (1,4,5)-trisphosphate (Ins(1,4,5)P3) which mobilizes
intracellular calcium. The mechanism by which Ins(1,4,5)P3
releases calcium will be investigated and special emphasis will be
placed on the regulation of this system by other cellular
constituents and hormones. Of particular interest in this respect
is the apparent potentiation by GTP of Ins(1,4,5)P3-induced
calcium release, which we and others have described. The calcium release system will be studied in preparations of
permeabilized hepatocytes and isolated sub-cellular fractions.
The hypothesis will be investigated that the calcium mobilization
system consists of an Ins(1,4,5)P3-activated calcium channel in
the endoplasmic reticulum, with associated regulatory proteins
whose activity can be modulated by guanine nucleotides. This
proposal will be tested by measurements of the kinetics of
calcium release and reuptake using fluorescent calcium indicators
and by examining the communication between different
intracellular pools of calcium. In addition to macroscopic calcium
transport measurements, microscopic and single channel calcium
currents will be measured using microsomes reconstituted into
planar lipid bilayers. These studies will give insight into the
physiological responses to the wide range of calcium-dependent
hormones which have important effects in almost all mammalian
cell types. Attempts will be made to identify the protein
components of the calcium release system by using photoaffinity
labels, with a view to longer term plans to reconstitute the
Ins(1,4,5)P3-sensitive calcium channel. A further focus of this
investigation will be the mechanisms by which the calcium-
mobilizing hormones interact with other classes of hormones such
as insulin.
StatusFinished
Effective start/end date3/1/883/31/04

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $290,120.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $283,213.00
  • National Institutes of Health

ASJC

  • Medicine(all)

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