The M-type voltage-gated potassium current regulates action potential threshold and spike frequency adaptation. The M current is suppressed by various neurotransmitters including acetylcholine, which elicits hyperexcitable periods upon stimulation. To date, a number of mutations in the genes encoding the M channel, KCNQ2, 3, 4 and 5, have been reported to cause neurological disorders such as epilepsy and neuromyotonia. Accordingly, M channel modulators are considered potential therapeutic agents to control neuronal excitability in pathogenic conditions such as epilepsy, pain and cognition. The long-term goal of this project is to elucidate regulation and physiological relevance of the M current modulation as a model for understanding roles of low threshold voltage-gated channels in higher brain function. Several parallel regulatory pathways have been identified for mediating the neurotransmitter-induced suppression of the M channel, one of which is depletion of PIP2 by activation of phospholipase C. Accumulating evidence shows PIP2 is an essential cofactor for a wide variety of ion channels and transporters. This general requirement for PIP2 raises the question of how PIP2 deletion selectively regulates the M channel. The hypothesis addressed in this proposal is that the M channel reduces its affinity to PIP2 due to rearrangement of the macromolecular channel complex during the neurotransmitter-induced suppression.
The specific aims are to: 1) link change in components of the M channel complex and reduction of PIP2 affinity during muscarinic cholinergic stimulation;2) elucidate changes in the M channel complex induced by calcium and cross talks with other pathways.
These aims will be tested by a combination of electrophysiological, biochemical and imaging approaches designed to address how the channel complex is arranged. Channel activity and conformational change will be recorded simultaneously using a patch clamp technique under FRET microscopy in transfected cultured cell lines and cultured neurons. This work will advance our understanding of how the M channel is regulated to control neuronal excitability.

Public Health Relevance

The present study is designed to identify regulatory mechanisms for the M-type potassium ion channel that are critical for setting nervous tone. The change in M-channel activities is related with nerve pain, epilepsy and cognition. This project will advance the understanding of these pathogenic conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS067288-05
Application #
8576472
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Silberberg, Shai D
Project Start
2010-01-15
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2014
Total Cost
$295,195
Indirect Cost
$102,257
Name
University of California Irvine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697