Sympathetic neuronal activity regulates such cardiovascular variables as heart rate, arterial blood pressure and myocardial contractility. The excitability of sympathetic neurons is determined in large part by a conductance known as the M-current. These investigators have recently determined that the M-current is encoded by the KCNQ2 and KCNQ3 genes. Increased understanding of these genes is a prerequisite to further investigation of 1) how the M-current is regulated during sympathetic activity, 2) the developmental control of this current and 3) the targeting of the M-current, and the pathways involved in its regulation, for pharmacological interventions in cardiovascular pathologies. The overall goal of the present application is to understand at a molecular level the subunit interactions that generate the constituent channels of the M-current. The projects outlined in Specific Aim 1 use knock-out and gain-of-function experiments to confirm our hypothesis that the M-current of sympathetic neurons is encoded by KCNQ2 and KCNQ3.
Specific Aim 2 would test the hypothesis that the formation of the M-current involves protein interaction between the KCNQ2 and KCNQ3 subunits.
Specific Aim 3 would test the corollary that protein interaction between the subunits facilitates the movement of subunit proteins from the endoplasmic reticulum to the cell membrane.
Specific Aim 4 would test the hypothesis that specific splice variants of the KCNQ2 and KCNQ3 genes encode the M-channel of sympathetic neurons.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061269-04
Application #
6637501
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
Wang, Lan-Hsiang
Project Start
2000-03-01
Project End
2004-08-31
Budget Start
2003-03-01
Budget End
2004-08-31
Support Year
4
Fiscal Year
2003
Total Cost
$277,221
Indirect Cost
Name
State University New York Stony Brook
Department
Physiology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794