Bisphosphonate-induced, hemichannel-mediated, anti-apoptosis through the Src/ERK pathway

A gap junction-independent action of connexin43

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Preservation of the mechanosensory function of osteocytes by inhibiting their apoptosis might contribute to the beneficial effects of bisphosphonates in bone. We report herein a mechanism by which connexin43 hemichannel opening by bisphosphonates triggers the activation of the kinases Src and ERKs and promotes cell survival. Bisphosphonate-induced anti-apoptosis requires connexin channel integrity, but not gap junctions. Osteocytic cells express functional hemichannels that are opened by bisphosphonates, as demonstrated by dye uptake, regulation by established agonists and antagonists, and cell surface biotinylation. The anti-apoptotic effect of bisphosphonates depends on connexin43 expression in mouse embryonic fibroblasts and osteoblastic cells. Transfection of connexin43, but not other connexins, into connexin43 naïve cells confers de novo responsiveness to the drugs. The signal transducing property of connexin43 requires the pore-forming, as well as the C-terminal domains of the protein, the interaction of connexin43 with Src, and the activation of both Src and ERK kinases. These studies establish a role for connexin43 hemichannels in bisphosphonate action, and a novel function of connexin43 - beyond gap junction communication - in the regulation of survival signaling pathways.

Original languageEnglish (US)
Pages (from-to)377-382
Number of pages6
JournalCell Communication and Adhesion
Volume8
Issue number4-6
StatePublished - 2001
Externally publishedYes

Fingerprint

Connexin 43
MAP Kinase Signaling System
Gap Junctions
Diphosphonates
Apoptosis
Connexins
src-Family Kinases
Chemical activation
Protein Interaction Domains and Motifs
Biotinylation
Osteocytes
Fibroblasts
Transfection
Cell Survival
Bone
Coloring Agents
Phosphotransferases
Communication
Cells
Bone and Bones

Keywords

  • Apoptosis
  • Bisphosphonates
  • Bone
  • Connexin43
  • ERKs
  • Src

ASJC Scopus subject areas

  • Cell Biology
  • Clinical Biochemistry

Cite this

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abstract = "Preservation of the mechanosensory function of osteocytes by inhibiting their apoptosis might contribute to the beneficial effects of bisphosphonates in bone. We report herein a mechanism by which connexin43 hemichannel opening by bisphosphonates triggers the activation of the kinases Src and ERKs and promotes cell survival. Bisphosphonate-induced anti-apoptosis requires connexin channel integrity, but not gap junctions. Osteocytic cells express functional hemichannels that are opened by bisphosphonates, as demonstrated by dye uptake, regulation by established agonists and antagonists, and cell surface biotinylation. The anti-apoptotic effect of bisphosphonates depends on connexin43 expression in mouse embryonic fibroblasts and osteoblastic cells. Transfection of connexin43, but not other connexins, into connexin43 na{\"i}ve cells confers de novo responsiveness to the drugs. The signal transducing property of connexin43 requires the pore-forming, as well as the C-terminal domains of the protein, the interaction of connexin43 with Src, and the activation of both Src and ERK kinases. These studies establish a role for connexin43 hemichannels in bisphosphonate action, and a novel function of connexin43 - beyond gap junction communication - in the regulation of survival signaling pathways.",
keywords = "Apoptosis, Bisphosphonates, Bone, Connexin43, ERKs, Src",
author = "Lilian Plotkin and Teresita Bellido",
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journal = "Cell Communication and Adhesion",
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TY - JOUR

T1 - Bisphosphonate-induced, hemichannel-mediated, anti-apoptosis through the Src/ERK pathway

T2 - A gap junction-independent action of connexin43

AU - Plotkin, Lilian

AU - Bellido, Teresita

PY - 2001

Y1 - 2001

N2 - Preservation of the mechanosensory function of osteocytes by inhibiting their apoptosis might contribute to the beneficial effects of bisphosphonates in bone. We report herein a mechanism by which connexin43 hemichannel opening by bisphosphonates triggers the activation of the kinases Src and ERKs and promotes cell survival. Bisphosphonate-induced anti-apoptosis requires connexin channel integrity, but not gap junctions. Osteocytic cells express functional hemichannels that are opened by bisphosphonates, as demonstrated by dye uptake, regulation by established agonists and antagonists, and cell surface biotinylation. The anti-apoptotic effect of bisphosphonates depends on connexin43 expression in mouse embryonic fibroblasts and osteoblastic cells. Transfection of connexin43, but not other connexins, into connexin43 naïve cells confers de novo responsiveness to the drugs. The signal transducing property of connexin43 requires the pore-forming, as well as the C-terminal domains of the protein, the interaction of connexin43 with Src, and the activation of both Src and ERK kinases. These studies establish a role for connexin43 hemichannels in bisphosphonate action, and a novel function of connexin43 - beyond gap junction communication - in the regulation of survival signaling pathways.

AB - Preservation of the mechanosensory function of osteocytes by inhibiting their apoptosis might contribute to the beneficial effects of bisphosphonates in bone. We report herein a mechanism by which connexin43 hemichannel opening by bisphosphonates triggers the activation of the kinases Src and ERKs and promotes cell survival. Bisphosphonate-induced anti-apoptosis requires connexin channel integrity, but not gap junctions. Osteocytic cells express functional hemichannels that are opened by bisphosphonates, as demonstrated by dye uptake, regulation by established agonists and antagonists, and cell surface biotinylation. The anti-apoptotic effect of bisphosphonates depends on connexin43 expression in mouse embryonic fibroblasts and osteoblastic cells. Transfection of connexin43, but not other connexins, into connexin43 naïve cells confers de novo responsiveness to the drugs. The signal transducing property of connexin43 requires the pore-forming, as well as the C-terminal domains of the protein, the interaction of connexin43 with Src, and the activation of both Src and ERK kinases. These studies establish a role for connexin43 hemichannels in bisphosphonate action, and a novel function of connexin43 - beyond gap junction communication - in the regulation of survival signaling pathways.

KW - Apoptosis

KW - Bisphosphonates

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KW - ERKs

KW - Src

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