Targeting voltage-gated Kv7/KCNQ/M-channel for therapeutic potential of neuropsychiatric disorders

doi:10.5246/jcps.2014.01.001

Abstract

Abstract:

M-type potassium current (I_M) was initially isolated from sympathetic neurons in 1980 and named as it was inhibited by muscarine. In 1998, the molecular identity of M-current was revealed to be heterotetramers of KCNQ2 and KCNQ3 subunits, whose mutations cause neonatal epilepsy. Reduction of voltage-gated KCNQ2/3 K⁺ channel (M-channel) activity leads to neuronal hyperexcitability that defines the fundamental mechanism of neurological disorders such as epilepsy and pain. Thus, suppression of neuronal hyperexcitability by activation of KCNQ2/3 channels serves the basis for development of the channel openers for treatment of epilepsy and pain. The well-known KCNQ opener is retigabine (Potiga) that was approved by FDA as an antiepileptic drug in 2011. Recent studies also provide evidence that KCNQ2/3 channel openers are effective in animal models of bipolar disorder, anxiety and schizophrenia, whereas KCNQ2/3 inhibitors, on the other hand, are indicated for improvement of learning and memory in animal models. We recently designed and validated a novel series of pyrazolo [1,5-a]pyrimidin-7(4H)-ones (PPOs) that selectively activate KCNQ2/3 and show antiepileptic and analgesic activity in vivo. Up to date, all the progress made enforces the view that targeting voltage-gated KCNQ/M-channel may provide therapeutic potential for treatment of neuropsychiatric disorders.

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Dr. KeWei Wang is currently an endowed ChangJiangProfessor and Chair of the Department of Molecular and Cellular Pharmacology at Peking University School of Pharmaceutical Sciences, where his overall research in the lab is directed towards understanding structure and molecular mechanisms of ion channels, and to identify and validate ion channel targets that are helpful for proving therapeutic potential of channel modulators for treatment of neuropsychiatric disorders.Currently, two classes of ion channels, voltage-gated potassium (Kv) and ligand-gated TRP channels,are investigated for their role in modulation of neurological function and pathology in the brain using cutting-edge technologies such as patch clamping electrophysiology and confocal Ca²⁺/FRET imaging with combination of molecular biology and in vivo pharmacology.
Dr. Wang graduated with M.D. in medicine and obtained his Ph.D. in neurophysiology from Peking University Medical School in 1988. From 1988 to 1997, he went to the University of Cambridge and then Yale University for postgraduate studies/training in disciplines of pharmacology, biophysics and physiology. From 1997 to 2006, he as a principal scientist/team leader worked on ion channel target related drug discovery/research for pain and pain-related neurological disorders at Wyeth Neuroscience, Princeton, New Jersey. He published over 60 peer-reviewed articles in journals such as Neuron, Nature Neurosci, PNAS, Nature, JBC, and Biophysiol J. etc, and was granted for 7 patents. Since 2008, he serves a review editor for several journals including “Front. Neurosci” and “Pharm. Sin. B”, etc..

Dr. Xiling Bian is currently a Lecturer in the Department of Molecular and Cellular Pharmacology at Peking University School of Pharmaceutical Sciences, where she is trying to identify the ion channel-targets of natural medicine and explore neurological functions of ion channels. Dr. Bian received her Ph.D. in neuroscience from Chinese Academy of Sciences in 2008 with her research topic ‘Pheromone-Processing Circuits in the Medial Amygdala’. After that, Dr. Bian entered Peking University Health Science Center. She has published four first (co-first) authored research articles in scientific journals such as Nature Communications. She received three grants, including one grant from National Natural Science Foundation of China and another one from Beijing City Youth Talent Plan. She was honored as Model Teacher of Peking University Health Science Center in 2011.

Key words: Kv7.2, Retigabine, XE991, Epilepsy, Pain

CLC Number:

R971

Supporting:

Xiling Bian, Kewei Wang*. Targeting voltage-gated Kv7/KCNQ/M-channel for therapeutic potential of neuropsychiatric disorders[J]. Journal of Chinese Pharmaceutical Sciences, 2014, 23(1): 5-15.

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