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Circulation Research. 2006;98:1365-1372
Published online before print May 11, 2006, doi: 10.1161/01.RES.0000225911.24228.9c
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(Circulation Research. 2006;98:1365.)
© 2006 American Heart Association, Inc.


Molecular Medicine

Identification of a Novel Peptide That Interferes With the Chemical Regulation of Connexin43

Junko Shibayama, Rebecca Lewandowski, Fabien Kieken, Wanda Coombs, Sejal Shah, Paul L. Sorgen, Steven M. Taffet*, Mario Delmar*

From the Departments of Pharmacology (J.S., R.L., W.C., S.S., M.D.) and Microbiology/Immunology (S.M.T.), State University of New York, Upstate Medical University, Syracuse; and Department of Biochemistry and Molecular Biology (F.K., P.L.S.), University of Nebraska Medical Center, Omaha.

Correspondence to Dr Mario Delmar, SUNY Upstate Medical University, Department of Pharmacology, 766 Irving Ave, Syracuse, NY 13210. E-mail delmarm{at}upstate.edu

The carboxyl-terminal domain of connexin43 (Cx43CT) is involved in various intra- and intermolecular interactions that regulate gap junctions. Here, we used phage display to identify novel peptidic sequences that bind Cx43CT and modify Cx43 regulation. We found that Cx43CT binds preferentially to peptides containing a sequence RXP, where X represents any amino acid and R and P correspond to the amino acids arginine and proline, respectively. A biased "RXP library" led to the identification of a peptide (dubbed "RXP-E") that bound Cx43CT with high affinity. Nuclear magnetic resonance data showed RXP-E–induced shifts in the resonance peaks of residues 343 to 346 and 376 to 379 of Cx43CT. Patch-clamp studies revealed that RXP-E partially prevented octanol-induced and acidification-induced uncoupling in Cx43-expressing cells. Moreover, RXP-E increased mean open time of Cx43 channels. The full effect of RXP-E was dependent on the integrity of the CT domain. These data suggest that RXP-based peptides could serve as tools to help determine the role of Cx43 as a regulator of function in conditions such as ischemia-induced arrhythmias.


Key Words: Cx43CT • connexin • particle-receptor interaction • gap junctions




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