HORMONAL CALCIUM MOBILIZATION/REGULATION IN THE LIVER

Project Details

Description

The effects of hormones such as catecholamines and vasopressin on
hepatic metabolism are mediated by alterations in the concentration of
cytosolic free Ca2+ ([Ca2+]c), largely as a result of Ca2+ mobilization
from intracellular stores by the second messenger inositol 1,4,5-
trisophosphate (IP3). The [Ca2+]c responses to these hormones are
organized in the form of [Ca2+]c oscillations and waves whose frequency
is controlled by agonist dose. Frequency-modulated [Ca2+]c oscillations
may serve a number of signaling functions, including improved fidelity,
sensitivity and targeted regulation of specific processes. [Ca2+}c waves
are also likely to play a role in propagating [Ca2+]c signals to distal
parts of the cell, in signaling between cells and in establishing
polarized functional responses. It is clear that the principal element
of the [Ca2+]c oscillation mechanism is the IP3 receptor Ca2+ channel
(IP3R), which is sensitive to positive and negative feedback regulation
by Ca2+ and IP3. However, the evidence also indicates that other Ca2+
signaling components may be involved in establishing the spatial and
temporal organization of [Ca2+]c signaling, either by modulating the
Ca2+ feedback regulation of the IP3R or by superimposing additional Ca2+
- feedback loops on the essential IP3R oscillator. We propose to
investigate how these additional inputs interact with IP3-dependent
[Ca2+]c oscillations to enrich the frequency range and spatial pattern
of oscillatory [CA2+]c waves. Our studies are designed to address the
following questions: 1. Does Ca2+ - feedback on IP3 metabolism
(phospholipase C or IP3 3-kinase) play a role in generating [Ca2+]c
oscillations and waves? 2. What is the role of the ryanodine receptor
in Ca2+ release and regenerative Ca2+ wave propagation? 3. What are
the consequences of the close coupling between IP3-dependent Ca2+
release and mitochondrial Ca2+ uptake for the temporal and spatial
organization of [Ca2+]c signals? 4. What defines the polarized
initiation site for [Ca2+]c waves in hepatocytes; subcellular
heterogeneity in IP3R function or spatially localized interactions of
the IP3R with other Ca2+ signaling components? These studies will make
use of biochemical, molecular and imaging techniques for studies of Ca2+
signaling in intact hepatocytes, together with a recently developed
permeabilized cell system in which we can reconstitute IP3-dependent
Ca2+ oscillations and waves.
StatusFinished
Effective start/end date4/1/943/31/04

Funding

  • National Institute of Diabetes and Digestive and Kidney Diseases: $290,120.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $283,213.00
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases

ASJC

  • Molecular Biology
  • Biochemistry
  • Cell Biology

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