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Abstract
Grant Number: 1R03MH076398-01 Project Title: Measurement of GPCR-mediated thallium flux:GIRK (RMI)
PI Information: Name Title NISWENDER, COLLEEN M. colleen.niswender@vanderbilt.edu Abstract: DESCRIPTION (provided by applicant): Pharmacological agents targeting G-protein coupled receptors and ion channels represent promising clinical agents spanning a multitude of human diseases. We have developed a screening strategy for Gi/o-linked receptors by measuring thallium flux through G protein regulated Inwardly Rectifying Potassium (K+) (GIRK) channels. Using this technique in HEK cells stably expressing GIRK 1 and 2 channels, we have generated preliminary data using muscarinic and adrenergic agonists and antagonists and have observed dose dependent regulation of these channels by endogenous M2/M4 receptors and ?2C adrenergic receptor selective agents. We have adapted this assay to a 384 well plate format and have performed initial Z' experiments that indicate that the assay is amenable to HTS. We propose to conduct a high throughput screen for novel agonists at the ?2C receptor; in the course of these studies, it is anticipated that we will identify novel agonists of GIRK 1/2 channels as well. Very few specific pharmacological tools exist targeting the ?2C receptor and due to its proposed role in psychiatric disorders and normal cardiac function it is anticipated that agonists targeting this receptor would provide critical tools to test ?2C receptor function in vivo. GIRK1/2 channels are known to be involved in neuronal excitability and it has been proposed that agonists for this receptor may provide new therapeutic avenues for epilepsy and pain. Lay summary: G-protein coupled receptors (GPCRs) and ion channels represent accessible therapeutic targets in human disease. We have developed a new assay, amenable to high throughput strategies, which can be used to screen large chemical libraries for compounds acting within the signal transduction pathway from receptor to ion channel. We propose to use this assay to identify compounds interacting with the ?2C adrenergic receptor as well as agents directly modulating the potassium channel employed in our assay system. Identified compounds will provide new pharmacological tools to test the role of the ?2C adrenergic receptor in psychiatric and cardiovascular disorders and the role of GIRK 1/2 channels in the modulation of neuronal excitability.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
cell surface receptor, drug screening /evaluation, high throughput technology, potassium channel, technology /technique development, thallium
adrenergic agent, alpha adrenergic receptor, antiadrenergic agent, receptor sensitivity
biotechnology
Institution: VANDERBILT UNIVERSITY Medical Center NASHVILLE, TN 372036869 Fiscal Year: 2005 Department: PHARMACOLOGY Project Start: 15-SEP-2005 Project End: 14-SEP-2006 ICD: NATIONAL INSTITUTE OF MENTAL HEALTH IRG: ZMH1