Hetero-domain interactions as a mechanism for the regulation of connexin channels

Kathleen Stergiopoulos, José Luis Alvarado, Marta Mastroianni, José F. Ek-Vitorin, Steven M. Taffet, Mario Delmar

Research output: Contribution to journalArticlepeer-review

121 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1144-1155
Number of pages12
JournalCirculation research
Issue number10
StatePublished - May 28 1999


  • Connexin
  • Hetero-domain interaction
  • Insulin
  • Xenopus oocyte
  • pH, regulation

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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