MOLECULAR PHYSIOLOGY OF GATING AND PERMEATION IN SODIUM AND CALCIUM CHANNELS

Project: Research project

Project Details

Description

Ion channels mediate normal and abnormal cardiac excitation. Sodium (Na)
and calcium (Ca) channels are particularly important in the pathogenesis
of sudden cardiac death because they support propagation of the cardiac
impulse and because they function as the receptors for a number of
clinically useful antiarrhythmic drugs. Project 1 examines the
fundamental structure-function correlation of Na and Ca channels. Using
molecular genetic methods to mutate and express ion channels, we will
investigate the structural basis of two fundamental channel processes,
permeation and inactivation. Permeation deals with ion translocation
through the channel pore, including the properties of ionic selectivity,
conductance and block. We will characterize the phenotypes of Na and Ca
channel point mutants in the loops between the fifth and sixth
transmembrane segments of each of the four channel domains. Wild-type
residues will be replaced by cysteine, producing an enhanced
susceptibility to block by group IIb divalent cations (cadmium and zinc).
The voltage dependence of block will be analyzed to determine fractional
electrical distances to the binding site created by the altered residue,
thereby enabling us to map the pore. Inactivation is the gating process
whereby channels enter a nonconducting state during maintained
depolarization. We will explore the sites involved in Na and Ca channel
inactivation and determine, by single-channel analysis, how selectively
and completely microscopic inactivation mutants. Having examined
permeation and gating individually, we will then carefully analyze pore
mutants for evidence of changes in inactivation, and inactivation mutants
for changes in permeation with a view to defining the structural overlap
between these two processes. Finally, we will determine how inactivation
mutants and selected permeation mutants alter the interaction of pore-
blocking drugs with Na and Ca channels.
StatusFinished
Effective start/end date10/1/969/30/97

Funding

  • National Heart, Lung, and Blood Institute

ASJC

  • Drug Discovery
  • Cardiology and Cardiovascular Medicine
  • Small Animals
  • Critical Care
  • Biophysics
  • Structural Biology
  • Physiology
  • Biochemistry
  • Advanced and Specialized Nursing
  • Internal Medicine
  • Pathology and Forensic Medicine
  • Microbiology
  • Pharmacology

Fingerprint Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.