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.
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.
|Greene, Derek L; Hoshi, Naoto (2016) Modulation of Kv7 channels and excitability in the brain. Cell Mol Life Sci :|
|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|
|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|
|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|
|Greene, Derek; Kang, Seungwoo; Kosenko, Anastasia et al. (2012) Adrenergic regulation of HCN4 channel requires protein association with Î²2-adrenergic receptor. J Biol Chem 287:23690-7|
|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 Î²1 subunit. Proc Natl Acad Sci U S A 109:18577-82|
|Smith, Ida M; Hoshi, Naoto (2011) ATP competitive protein kinase C inhibitors demonstrate distinct state-dependent inhibition. PLoS One 6:e26338|