Summary of probe development for inhibitors of KCNQ2 potassium channel
Assay Implementation: Haibo Yu Ph.D., Beiyan Zou Ph.D., Shunyou Long M.S., Amy Scott, Meng Wu Ph.D., Joseph Babcock, Bill Shi Ph.D., David Meyers Ph.D., Jia Xu Ph.D. ..more
Depositor Specified Assays
Source (MLPCN Center Name): Johns Hopkins Ion Channel Center (JHICC)
Center Affiliation: Johns Hopkins University, School of Medicine
Screening Center PI: Min Li, Ph.D.
Assay Provider: Min Li, Ph.D.
Network: Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: 1 R03 DA027716-01
Grant Proposal PI: Min Li, Ph.D., Johns Hopkins University School of Medicine
Assay Implementation: Haibo Yu Ph.D., Beiyan Zou Ph.D., Shunyou Long M.S., Amy Scott, Meng Wu Ph.D., Joseph Babcock, Bill Shi Ph.D., David Meyers Ph.D., Jia Xu Ph.D.
Voltage-gated potassium (K) channels are critical for neuronal function in excitable tissues such as brain and heart. They are also found in non-excitable tissues important for other functions such as hormone secretion, oxygen-sensing and immune responses. There are more than 100 genes in human genome encoding different but homologous potassium channels. Voltage-gated K+ channels, exemplified by the Shaker K+ channel, share considerable sequence similarity. Isolation and characterization of bioactive chemical probes could form important pharmacological foundation, providing a great deal of insights into the structure and function.
The KCNQ (or also called Kv7) channel family includes five members, KCNQ1 to KCNQ5; KCNQ are members of Kv channel superfamily[1-6]. Different from other Kv channel classes, KCNQ channels commonly display a sub-threshold opening (i.e., at a voltage near resting potential) and are regulated by GPCR signaling, e.g., muscarinic receptors [7, 8]. KCNQ2-5 channels are primarily expressed in the brain, while KCNQ1 is abundantly expressed in cardiac tissue. Among congenital long QT patients, a disease which affects 1 in 2,500 live births, the most prevalent mutations are within the KCNQ1 allele. Mutations in KCNQ2 and KCNQ3 are known to cause benign familial neonatal convulsion (BFNC), a rare form of epilepsy .
In the mid-90s, a compound known as D-23129, or retigabine, was initially developed to target GABAnergic signaling [10, 11]. Despite its poor effect on the GABA pathway, retigabine was shown to have potent anti-convulsant activity. In 1997, retigabine was also found to induce the opening of voltage-gated potassium channels at resting membrane potentials, and since then, through a variety of other studies, this has been established to be its main mechanism of action. Retigabine, acting on KCNQ2/3 potassium channels which code M-currents, is now being used for treatment of epilepsy. None of the anti-convulsants that are in clinical use today have a comparable mechanism of action, i.e., through ligand activation of voltage-gated potassium channels. Several potentiation compounds are synthesized according to the scaffold of retigabine. However, considering the poor potency of retigabine and several other undesirable characteristics including its broad action on KCNQ2, 3, 4, and 5 , it is not clear whether these related structures will fundamentally improve therapeutic efficacy. Hence, it argues for the performance of a non-biased screen for new structures with potentiation activity.
This assay summarizes the efforts of identifying and developing small chemical compounds that inhibit the KCNQ2 potassium channels.
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