New Modes of GPCR Signalling

Isoform-Specific Prolongation of KCNQ (Kv7) Potassium Channel
Opening Mediated by a New Drug-Channel Binding Site
Zhaobing Gao1, 5, Tangzhi Zhang2, Meng Wu1, Qiaojie Xiong1, 3, Haiyan Sun1, 4,
Yinan Zhang2, Liansuo Zu2, Wei Wang2,* and Min Li1,*
1Department of Neuroscience, High Throughput Biology Center and Johns Hopkins
Ion Channel Center, School of Medicine, Johns Hopkins University, 733 North
Broadway, Baltimore, MD 21205, 2Department of Chemistry & Chemical Biology,
University of New Mexico, Albuquerque, NM 87131, 3 Current address: Cold Spring
Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, 4 Current
address: Corning Inc. One Science Center Road, Corning, NY 14831, 5 Current address:
Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences,
Chinese Academy of Sciences, Shanghai 201203
Kv7 channels, especially Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3), are key determinants
for membrane excitability. Some chemical modulators for KCNQ are being approved
for therapeutic use as anti-epileptic drugs, such as retigabine ((D-23129,
N-(2-amino-4-(4-fluorobenzylamino)-phenyl). Therefore, a better understanding of
Compound-channel interaction is an area of intense interest. Of particular interest, a
single residue change of W236L in KCNQ2 abolishes its sensitivity to Retigabine. We
have conducted a screen of 20,000 compounds for KCNQ potentiators using rubidium
flux combined with atomic absorption spectrometry (AAS). Here, we report
characterization of a series of new structures with structural similarity to ICA-27243.
We found that they display isoform specificity and induce a marked reduction of
deactivation distinct from that of retigabine. Furthermore, KCNQ2(W236L) remains
fully sensitive to these compounds. This result together with mutagenesis studies and
analyses of combinatorial drug treatments suggests ZTZ compounds confers a new
mode of action presumably by recognizing a new site on channel protein. Our results
argue for a rationale for a deliberate search for channel potentiators with preferential
effects of inhibiting channel close.
Key Words: Potassium Channel, KCNQ, Activator, High Throughput Screening
* To whom the correspondence should be addressed:
Wei Wang, Ph.D., Department of Chemistry & Chemical Biology, University of New
Mexico, Albuquerque, NM 87131. 505-277-2609 (fax). wwang@unm.edu
Min Li, Ph.D., Department of Neuroscience, Johns Hopkins University School of
Medicine, BRB311, 733 North Broadway, Baltimore, MD 21205. 410-614-1001 (fax).
minli@jhmi.edu