Connexin43 interacts with βarrestin: A pre-requisite for osteoblast survival induced by parathyroid hormone

Nicoletta Bivi, Virginia Lezcano, Milena Romanello, Teresita Bellido, Lilian I. Plotkin

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

Parathyroid hormone (PTH) promotes osteoblast survival through a mechanism that depends on cAMP-mediated signaling downstream of the G protein-coupled receptor PTHR1. We present evidence herein that PTH-induced survival signaling is impaired in cells lacking connexin43 (Cx43). Thus, expression of functional Cx43 dominant negative proteins or Cx43 knock-down abolished the expression of cAMP-target genes and anti-apoptosis induced by PTH in osteoblastic cells. In contrast, cells lacking Cx43 were still responsive to the stable cAMP analog dibutyril-cAMP. PTH survival signaling was rescued by transfecting wild type Cx43 or a truncated dominant negative mutant of βarrestin, a PTHR1-interacting molecule that limits cAMP signaling. On the other hand, Cx43 mutants lacking the cytoplasmic domain (Cx43 Δ245) or unable to be phosphorylated at serine 368 (Cx43 S368A), a residue crucial for Cx43 trafficking and function, failed to restore the anti-apoptotic effect of PTH in Cx43-deficient cells. In addition, overexpression of wild type βarrestin abrogated PTH survival signaling in Cx43-expressing cells. Moreover, βarrestin physically associated in vivo to wild type Cx43 and to a lesser extent to Cx43 S368A; and this association and the phosphorylation of Cx43 in serine 368 were reduced by PTH. Furthermore, induction of Cx43 S368 phosphorylation or overexpression of wild type Cx43, but not Cx43 Δ245 or Cx43 S368A, reduced the interaction between βarrestin and the PTHR1. These studies demonstrate that βarrestin is a novel Cx43-interacting protein and suggest that, by sequestering βarrestin, Cx43 facilitates cAMP signaling, thereby exerting a permissive role on osteoblast survival induced by PTH.

Original languageEnglish (US)
Pages (from-to)2920-2930
Number of pages11
JournalJournal of Cellular Biochemistry
Volume112
Issue number10
DOIs
StatePublished - Oct 2011

Keywords

  • βarrestin
  • Cx43
  • osteoblast survival
  • PTH

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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