Our long term goal is to understand the pathophysiological role of voltage-dependent Ca2+ channels in epilepsy and other neurological disorders. Among the four subunits comprising the mammalian Ca2+ channel (alpha1, alpha2delta, beta, gamma), the gamma subunit is the least well understood. Originally copurified with the 1,4-dihydropyridine receptor (L-type Ca2+ channel) from skeletal muscle, early studies centered on the ability of the 32 kDa transmembrane gamma subunit to modulate the electrophysiological properties of the channel. Other possible functions went largely unexplored. A focus on the regulation of Ca2+ currents as the function of the gamma subunit continued after identification of a novel neuronal isoform (CACNG2, gamma2) that is mutated in the stargazer (stg) mouse, a valuable animal model of inherited epilepsy and ataxia. Our laboratory has now identified 6 more Ca2+ channel gamma subunit genes: CACNG3-CACNG8. It was recently determined that the gamma2 subunit interacts with PDZ domain proteins (PSD-95 and others) and is essential for the proper membrane localization and synaptic targeting of AMPA-type glutamate receptors in cerebellar neurons. Based on these data, and preliminary analysis of CACNG3-CACNG8, we hypothesize that Ca2+ channel gamma subunits are primarily involved in the formation and targeting of multifunctional synaptic protein complexes in neurons, and that regulation of Ca2+ currents may be only a subsidiary function.
The specific aims of this project are to: 1) determine the spatial and developmental expression of the wild-type Ca2+ channel gamma subunit genes (CACNG 1-8) and proteins (gamma1-8) in brain; 2) characterize binding of the gamma subunits to (a) PDZ domain proteins, (b) each other, and (c) novel proteins; and 3) determine whether loss of the gamma2 subunit in the Cacng2-null stargazer (stg) mouse results in altered expression of Cacng1-8 in brain, or altered steady-state association of gamma3, gamma4, and gamma8 with PDZ domain proteins. These systematic studies will provide invaluable insight into the basic function of the Ca2+ channel gamma subunits, the structure and localization of protein complexes at neuronal synapses, and the molecular mechanisms of inherited epilepsy and ataxia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042632-02
Application #
6620374
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Fureman, Brandy E
Project Start
2001-12-15
Project End
2006-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
2
Fiscal Year
2003
Total Cost
$321,694
Indirect Cost
Name
Baylor College of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030