The long-term objective of this research is to understand the molecular and structural mechanisms of the function of transient receptor potential (TRP) channels. In particular, we will focus on the canonical TRP (TRPC) channels, which are present in blood vessels, heart, lung, kidney and brain and are involved in regulating diverse biological processes ranging from neural and cardiovascular functions to sexual behavior. The seven members of the TRPC channel family conduct calcium into cells and are in turn regulated by intracellular calcium. All TRPC proteins interact directly with calmodulin (CaM), a ubiquitous calcium sensing protein, which may mediate calcium-dependent feedback regulation of TRPC channel activity and function.
Our specific aims are to solve the high-resolution crystal structure of the complex of CaM and each of the four putative CaM-binding sites in TRPC proteins and to study the molecular mechanism and functional impact of CaM binding to each site. Our central hypothesis is that CaM forms distinct interactions with each TRPC site and these interactions regulate channel properties and functions in a channel-specific fashion. Mutations in TRPC channels have been linked to focal and segmental glomerulosclerosis, a hereditary kidney disorder leading to renal failure, and the abundance of TRPC channels in airway smooth muscles and blood vesicles suggest that their malfunction could play a role in asthma, chronic obstructive pulmonary disease, hypertension and various types of cardiovascular diseases. Thus, our studies will not only provide a better understanding of the function and regulation of these biologically important ion channels but also facilitate the development of new therapeutic strategies for the treatment of a host of human diseases.

Public Health Relevance

TRPC channels are found in blood vessels, heart, lung, kidney and brain and are involved in regulating numerous biological processes ranging from neural and cardiovascular functions to sexual behavior. Malfunction of these channels may cause human diseases such as asthma and various types of cardiovascular diseases. A better understanding of how these channels work may provide new ways to treat a host of human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045383-13
Application #
7768376
Study Section
Special Emphasis Panel (ZRG1-MDCN-P (02))
Program Officer
Silberberg, Shai D
Project Start
1997-07-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
13
Fiscal Year
2010
Total Cost
$348,666
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
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