© 1999 American Heart Association, Inc.
Original Contribution |
Hetero-Domain Interactions as a Mechanism for the Regulation of Connexin Channels
From the Departments of Pharmacology (K.S., J.L.A., M.M., J.F.E.-V., M.D.) and Microbiology and Immunology (S.M.T.), SUNY Health Science Center, Syracuse, NY.
Correspondence to Mario Delmar, MD, PhD, Department of Pharmacology, SUNY Health Science Center, 766 Irving Ave, Syracuse, NY 13210. E-mail delmarm{at}vax.cs.hscsyr.edu
Abstract—Previous studies have shown that chemical regulation of connexin43 (Cx43) depends on the presence of the carboxyl terminal (CT) domain. A particle-receptor (or "ball-and-chain") model has been proposed to explain the mechanism of gating. We tested whether the CT region behaved as a functional domain for other members of the connexin family. The pH sensitivity of wild-type and Ct-truncated connexins was quantified by use of electrophysiological and optical techniques and the Xenopus oocyte system. The CT domain of Cx45 had no role in pH regulation, although a partial role was shown for Cx37 and Cx50. A prominent effect was observed for Cx40 and Cx43. In addition, we found that the CT domain of Cx40 that was expressed as a separate fragment rescued the pH sensitivity of the truncated Cx40 (Cx40tr), which was in agreement with a particle-receptor model. Because Cx40 and Cx43 often colocalize and possibly heteromerize, we tested the pH sensitivity of Cx40tr when coexpressed with the CT domain of Cx43 (hetero-domain interactions). We found that the CT domain of Cx43 enhanced the pH sensitivity of Cx40tr; similarly, the CT domain of Cx40 restored the pH sensitivity of the truncated Cx43. In addition, the CT domain of Cx43 granted insulin sensitivity to the otherwise insulin-insensitive Cx26 or Cx32 channels. These data show that the particle-receptor model is preserved in Cx40 and the regulatory domain of one connexin can specifically interact with a channel formed by another connexin. Hetero-domain interactions could be critical for the regulation of heteromeric channels.
Key Words: connexin • pH, regulation • insulin • Xenopus oocyte • hetero-domain interaction
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