Because of their involvement in every aspect of neuronal physiology, K+ channels of different families are regarded as potential drug targets for the treatment of various neurological disorders. K+ channel modulators may be effective in treatment of epilepsy, stroke, schizophrenia, depression and neurodegenerative disorders. Finding and characterizing new K+ channel modulators is therefore an obvious priority in neuropharmacology. However, discovery of new K+ channel modulators is limited by the low throughput capacity of existing electrophysiology-based drug screens. To overcome this limitation we are proposing a novel high throughput screening strategy based on functional expression of mammalian K+ channel Kir2.1 in yeast. Compounds that inhibit or enhance growth of yeast expressing Kir2.1 channel are selected as potential K+ channel modulators and examined in mammalian cells by patch-clamp technique. Yeast-based primary assay allows screening of chemical libraries with virtually unlimited number of compounds.
The specific aims of the proposal are: 1) to perform a large scale screen of over 100,000 compounds in 4 structurally distinct chemical libraries in yeast expressing Kir2.1 channel, 2) to identify K+ channel modulators by examining action of compounds discovered in Aim 1 on Kir2.1 currents in mammalian cells, 3) to examine action of new modulators on a variety of K+ channels associated with neurological disorders and identify the most potent and specific K+ channel modulators. The study will prove the feasibility and evaluate the efficacy of the yeast-based screen. It will also provide leads for future search for highly specific and potent K+ channel modulators for use as neuropharmacological agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS048089-02
Application #
6848010
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
2004-02-01
Project End
2007-01-31
Budget Start
2005-02-01
Budget End
2007-01-31
Support Year
2
Fiscal Year
2005
Total Cost
$171,703
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Salvador-Recatala, Vicenta; Kim, Yonjung; Zaks-Makhina, Elena et al. (2006) Voltage-gated k+ channel block by catechol derivatives: defining nonselective and selective pharmacophores. J Pharmacol Exp Ther 319:758-64
Grishin, Anatoly; Ford, Henri; Wang, Jin et al. (2005) Attenuation of apoptosis in enterocytes by blockade of potassium channels. Am J Physiol Gastrointest Liver Physiol 289:G815-21