Ca(2+) regulation of connexin 43 hemichannels in C6 glioma and glial cells

Elke De Vuyst, Elke Decrock, Marijke De Bock, Nan Wang, Mathieu Vinken, Marijke Van Moorhem, Charles Lai, Maxime Culot, Vera Rogiers, Romeo Cecchelli, Christian Naus, Howard Evans, Luc Leybaert

Research output: Contribution to journalArticle

156 Citations (Scopus)

Abstract

Connexin hemichannels have a low open probability under normal conditions but open in response to various stimuli, forming a release pathway for small paracrine messengers. We investigated hemichannel-mediated ATP responses triggered by changes of intracellular Ca(2+) ([Ca(2+)](i)) in Cx43 expressing glioma cells and primary glial cells. The involvement of hemichannels was confirmed with gja1 gene-silencing and exclusion of other release mechanisms. Hemichannel responses were triggered when [Ca(2+)](i) was in the 500nM range but the responses disappeared with larger [Ca(2+)](i) transients. Ca(2+)-triggered responses induced by A23187 and glutamate activated a signaling cascade that involved calmodulin (CaM), CaM-dependent kinase II, p38 mitogen activated kinase, phospholipase A2, arachidonic acid (AA), lipoxygenases, cyclo-oxygenases, reactive oxygen species, nitric oxide and depolarization. Hemichannel responses were also triggered by activation of CaM with a Ca(2+)-like peptide or exogenous application of AA, and the cascade was furthermore operational in primary glial cells isolated from rat cortex. In addition, several positive feed-back loops contributed to amplify the responses. We conclude that an elevation of [Ca(2+)](i) triggers hemichannel opening, not by a direct action of Ca(2+) on hemichannels but via multiple intermediate signaling steps that are adjoined by distinct signaling mechanisms activated by high [Ca(2+)](i) and acting to restrain cellular ATP loss.
Original languageEnglish
Pages (from-to)176-187
Number of pages12
JournalCell Calcium
Volume46
Publication statusPublished - 1 Sep 2009

Keywords

  • connexin
  • ATP

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