) Ca2+ entry through voltage-gated Ca2+ channels in nerve terminals initiates the release of neurotransmitter at a synapse. Because small fluctuations in Ca2+ levels correlate with large changes in synaptic efficacy, regulation of Ca2+ influx through presynaptic Ca2+ channels can powerfully influence neurotransmision. Ca2+ currents through presynaptic P/Q type-channels undergo Ca2+-dependent facilitation that contributes to the short-term enhancement of synaptic transmission, but little is known about the underlying mechanism. The Ca2+-dependent properties of a number of ion channels are conferred directly by calmodulin, which also binds to the alpha1A-subunit of P/Q-type Ca2+ channels. Thus, the studies in this proposal will test the hypothesis that calmodulin binding to the alpha1A subunit mediates the feedback regulation of P/Q-type channels by Ca2+. Techniques in molecular biology and electrophysiology will be used to characterize the molecular determinants and functional impact of the calmodulin/Ca2+ channel interaction with respect to Ca2+-dependent facilitation of P/Q-type Ca2+ channels transfected in mammalian cells. The goal of the proposed studies is to elucidate how presynaptic Ca2+ channel modulation contributes to the fine-tuning of neurotransmission, which may be a first step in understanding the clinical manifestations of P/Q-type Ca2+ channel defects, such as epilepsy and migraine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
2F32NS010645-03
Application #
6140076
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Talley, Edmund M
Project Start
2000-06-01
Project End
Budget Start
2000-03-16
Budget End
2001-09-15
Support Year
3
Fiscal Year
2000
Total Cost
$37,516
Indirect Cost
Name
University of Washington
Department
Pharmacology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lee, Amy; Westenbroek, Ruth E; Haeseleer, Francoise et al. (2002) Differential modulation of Ca(v)2.1 channels by calmodulin and Ca2+-binding protein 1. Nat Neurosci 5:210-7