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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Silberberg, Shai D
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University of California Irvine
Schools of Medicine
United States
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Greene, Derek L; Kosenko, Anastasia; Hoshi, Naoto (2018) Attenuating M-current suppression in vivo by a mutant Kcnq2 gene knock-in reduces seizure burden and prevents status epilepticus-induced neuronal death and epileptogenesis. Epilepsia 59:1908-1918
Greene, Derek L; Kang, Seungwoo; Hoshi, Naoto (2017) XE991 and Linopirdine Are State-Dependent Inhibitors for Kv7/KCNQ Channels that Favor Activated Single Subunits. J Pharmacol Exp Ther 362:177-185
Greene, Derek L; Hoshi, Naoto (2017) Modulation of Kv7 channels and excitability in the brain. Cell Mol Life Sci 74:495-508
Kay, Hee Yeon; Greene, Derek L; Kang, Seungwoo et al. (2015) M-current preservation contributes to anticonvulsant effects of valproic acid. J Clin Invest 125:3904-14
Jiang, Ling; Kosenko, Anastasia; Yu, Clinton et al. (2015) Activation of m1 muscarinic acetylcholine receptor induces surface transport of KCNQ channels through a CRMP-2-mediated pathway. J Cell Sci 128:4235-45
Kang, Seungwoo; Xu, Mingxuan; Cooper, Edward C et al. (2014) Channel-anchored protein kinase CK2 and protein phosphatase 1 reciprocally regulate KCNQ2-containing M-channels via phosphorylation of calmodulin. J Biol Chem 289:11536-44
Kosenko, Anastasia; Hoshi, Naoto (2013) A change in configuration of the calmodulin-KCNQ channel complex underlies Ca2+-dependent modulation of KCNQ channel activity. PLoS One 8:e82290
Kosenko, Anastasia; Kang, Seungwoo; Smith, Ida M et al. (2012) Coordinated signal integration at the M-type potassium channel upon muscarinic stimulation. EMBO J 31:3147-56
Nguyen, Hai M; Miyazaki, Haruko; Hoshi, Naoto et al. (2012) Modulation of voltage-gated K+ channels by the sodium channel ?1 subunit. Proc Natl Acad Sci U S A 109:18577-82
Greene, Derek; Kang, Seungwoo; Kosenko, Anastasia et al. (2012) Adrenergic regulation of HCN4 channel requires protein association with ?2-adrenergic receptor. J Biol Chem 287:23690-7

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