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(Circulation Research. 2009;105:176.)
© 2009 American Heart Association, Inc.

Cellular Biology

Novel Pharmacophores of Connexin43 Based on the "RXP" Series of Cx43-Binding Peptides

Vandana Verma, Bjarne Due Larsen, Wanda Coombs, Xianming Lin, Gaelle Spagnol, Paul L. Sorgen, Steven M. Taffet, Mario Delmar

From the Center for Arrhythmia Research (V.V., X.L., M.D.), Department of Internal Medicine, University of Michigan, Ann Arbor; Zealand Pharma (B.D.L.), Glostrup, Denmark; Department of Microbiology and Immunology (W.C., S.M.T.), Upstate Medical University, State University of New York, Syracuse; and Department of Biochemistry and Molecular Biology (G.S., P.L.S.), University of Nebraska Medical Center, Omaha.

Correspondence to Address correspondence to: Mario Delmar, MD, PhD, Center for Arrhythmia Research, University of Michigan Medical School, 5025 Venture Dr, Ann Arbor MI 48104. E-mail mdelmar{at}umich.edu

Gap junction pharmacology is a nascent field. Previous studies have identified molecules that enhance intercellular communication, and may offer potential for innovative antiarrhythmic therapy. However, their specific molecular target(s) and mechanism(s) of action remain unknown. Previously, we identified a 34-aa peptide (RXP-E) that binds the carboxyl terminal domain of Cx43 (Cx43CT) and prevents cardiac gap junction closure and action potential propagation block. These results supported the feasibility of a peptide-based pharmacology to Cx43, but the structure of the core active element in RXP-E, an essential step for pharmacological development, remained undefined. Here, we used a combination of molecular modeling, surface plasmon resonance, nuclear magnetic resonance and patch-clamp strategies to define, for the first time, a unique ensemble of pharmacophores that bind Cx43CT and prevent closure of Cx43 channels. Two particular molecules are best representatives of this family: a cyclized heptapeptide (called CyRP-71) and a linear octapeptide of sequence RRNYRRNY. These 2 small compounds offer the first structural platform for the design of Cx43-interacting gap junction openers. Moreover, the structure of these compounds offers an imprint of a region of Cx43CT that is fundamental to gap junction channel function.

Key Words: gap junctions • arrhythmias • connexin 43