Identification of ischemia-regulated phosphorylation sites in connexin43: A possible target for the antiarrhythmic peptide analogue rotigaptide (ZP123).

Research output: Contribution to journalJournal articleResearchpeer-review

  • Lene Nygaard Axelsen
  • Martin Stahlhut
  • Shabaz Mohammed
  • Bjarne Due Larsen
  • Nielsen, Morten Schak
  • Søren Andersen
  • Ole N Jensen
  • James K Hennan
  • Anne Louise Kjølbye
  • N.-H. Holstein-Rathlou
Previous studies suggest that dephosphorylation of connexin43 (Cx43) is related to uncoupling of gap junction communication, which plays an important role in the genesis of ischemia-induced ventricular tachycardia. We studied changes in Cx43 phosphorylation during global ischemia in the absence and presence of the antiarrhythmic peptide analogue rotigaptide (formerly known as ZP123). Phosphorylation analysis was performed on Cx43 purified from isolated perfused rat hearts using matrix-assisted laser desorption/ionization mass spectrometry and liquid chromatography electrospray ionization tandem mass spectrometry. Thirteen different serine phosphorylation sites were identified in Cx43 during non-ischemic conditions, three of which had not previously been described. Within the first 7 min of ischemia, Ser306 became fully dephosphorylated whereas Ser330 became phosphorylated. Between 15 and 30 min of ischemia, the critical time interval where gap junction uncoupling occurs, Ser297 and Ser368 also became fully dephosphorylated. During the same time period, all untreated hearts developed asystole. Treatment with rotigaptide significantly increased the time to ischemia-induced asystole and suppressed dephosphorylation of Ser297 and Ser368 at 30 min of ischemia. Our results suggest that phosphorylation of Ser297 and Ser368 may be involved in functional gating of Cx43 during ischemia and may be possible downstream targets for rotigaptide signaling.
Original languageEnglish
JournalJournal of Molecular and Cellular Cardiology
Volume40
Issue number6
Pages (from-to)790-8
Number of pages8
ISSN0022-2828
DOIs
Publication statusPublished - 2006

Bibliographical note

Keywords: Amino Acid Sequence; Animals; Connexin 43; Heart Arrest; Male; Molecular Sequence Data; Myocardial Ischemia; Oligopeptides; Phosphorylation; Phosphotransferases; Rats; Rats, Sprague-Dawley; Serine

ID: 8419949