Voltage-gated Na+ channels underlie the upstroke of the action potential in strained muscle and nerve cells. Mutations in the Na+ channel protein that alter both fast and slow gating processes that have been shown to underlie several hereditary muscle diseases. We now have evidence that both fast and slow gating processes in Na+ channels are regulated by the concentration and identity of extracellular cations. The long term goal of the research is a mechanistic understanding of this modularity phenomenon. The primary experimental approach is to record whole-cell and single- channel Na+ currents after heterologous expression in mammalian cells or Xenopus oocytes. Analysis of Na+ currents obtained in the presence of internal and external fast blockers of open channels will help determine whether the effects of extracellular cations are mediated through interactions with the channel pore. Peak open probability and slow activation will be examined in whole cell and single channel records. A pore mutation that abolishes slow inactivation in rat skeletal muscle Na+ channels (W374C) will be examined. Additional cysteine mutations of residues known to be critical for selectivity of Na+ channels will also be studies. Cysteine-modifying reagents will be used to explore the roles of the native pore residue C373 and the introduced cysteines on both permeation and modulation and Na+ channel gating by extracellular cations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32NS010439-01
Application #
2411270
Study Section
Physiology Study Section (PHY)
Project Start
1998-01-01
Project End
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Physiology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107