CALCIUM REGULAORY MECHANISMS IN NEURAL CELLS

Project: Research project

Project Details

Description

Ca++ is a fundamental regulator of many essential neural functions and the
plasma membrane of neural cells is preeminent among cellular sites for
controlling internal Ca++ levels. The studies described in ths application
are a comprehensive analysis of the Ca2+ regulatory mechanism operating in
the neural plasma membrane. The approach is based on preliminary studies
characterizing the isolation and properties of a preparation of
synaptosomal plasma membrane vesicles. This methodology provides the
unique capability of analyzing biochemically the transport and regulatory
mechanisms that control Ca++ fluxes across the neural plasma membrane, and
relating their activity ot the control of Ca++ in the intact neural cell.
The studies on Ca++ regulation utilize two different neurological systems
from which to derive plasma membrane vesicles: (1) synaptosomes isolated
from rat brain cerebral cortex; (2) homogeneous cloned neural cell lines,
selected for their specific receptor-mediated control propeties
(neuroblastoma N1E-115 and neuroblastoma-glioma NG108-15 cell lines).
Initial studies concern refinement of procedures for isolation of vesicles
of high plasma membrane purity and defined sidedness, from each system, and
precise characterization of the Ca++ flux mechanisms within them. Major
studies concern analysis of the regulatory mechanisms which critically
control the activity of the Ca++ fluxes across the plasma membrane. These
involve both the direct receptor-mediated modulation of Ca++ transport (in
particular, via the muscarinic receptor) and the important internal
regulatory mechanisms exerted by intracellular regulators (cyclic AMP and
calmodulin) through phosphorylation of specific plasma membrane regulatory
proteins. The plasma membrane is a primary site for pharmacological
control. The studies permit a direct examination of the effects of several
important classes of neuroactive pharmacological agents (including
anticonvulsants, narcotic analgesics, antipsychotics, and anesthetics)
which are believed to exert their neurological effects through direct
modification of plasma membrane Ca++ fluxes or their regulatory
components. An in depth understanding of the mechanisms which control Ca++
entry and efflux, their physiological regulation, and their pharmacological
modification, is essential to determining effective counteractive therapy
for diseases either affecting chemical transmission (Parkinson's disease
and myasthenia gravis) or those altering neural conduction (including
multiple scelorosis).
StatusFinished
Effective start/end date4/1/8312/31/94

Funding

  • National Institutes of Health
  • National Institutes of Health: $183,987.00

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