CaV1.3 channels are low-threshold, dihydropyridine-sensitive L-type Ca2+ channels which mediate low-voltage signaling and rhythmicity throughout the body. They are essential for neurotransmitter release at ribbon synapses such as found in cochlear hair cells;they mediate pacemaking in the heart;and they modulate oscillatory behavior throughout the brain, such as the repetitive bursting in supra-chiasmatic (circadian pacemaking circuitry) and substantia nigra (locus of primary damage in Parkinson's) nuclei. As such, overactivity of these channels may predispose for Ca2+ overload precipitating Parkinson's, and downward modulation of these channels may enhance positive mood and affect. Clearly, small-molecule compounds that selectively inhibit or enhance CaV1.3 channels, rather than the other CaV1 L-type channels would be of enormous utility for basic studies of CaV1.3 roles, and for potentially amerliorating a number of CaV1.3-related pathologies. However, though excellent L-type channels antagonists and agonists have been discovered, none can truly select among the L-type channel subtypes. Here, in the search for selective modulators, we will exploit a unique molecular interaction between ICDI and IQ domains of CaV1.3 channels, where this interaction modulates the strength Ca2+ feedback inhibition (CDI) of these channels. This promising screen will be prosecuted according to three specific aims. 1) To perform a primary screen for small molecules that disrupt or enhance a functionally critical interaction between IQ and ICDI domains of CaV1.3 channels, using the MLSMR library of 350,000-500,00 compounds. 2) To confirm and identify candidate hits from Aim 1 using a microscope-based FRET analysis of single living cells. 3) To test candidate compounds for modulation of CaV1.3 Ca2+ regulation, using patch-clamp electrophysiology. Overall, this project promises lead candidates for selective modulators of CaV1.3 versus other CaV1 L-type calcium channels.

Public Health Relevance

PI: David Yue, MD, PhD CaV1.3 calcium channels mediate rhythmicity throughout heart and brain, and their overactivity may predispose for Parkinson's and other neurodegenerative diseases. Yet, there are no selective small-molecular modulators of CaV1.3 versus other CaV1 L-type channels. This proposal will screen for selective small-molecule modulators of CaV1.3 channels, exploiting recently discovered molecular features of these channels that are structurally unique.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Small Research Grants (R03)
Project #
1R03MH098699-01
Application #
8408867
Study Section
Special Emphasis Panel (ZRG1-BST-F (50))
Program Officer
Yao, Yong
Project Start
2012-09-10
Project End
2014-07-31
Budget Start
2012-09-10
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$40,500
Indirect Cost
$15,500
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218