Connexins regulate calcium signaling by controlling ATP release

TLDR

Forced expression of connexins enables gap junction‑deficient cell lines to propagate intercellular calcium waves. ATP release depends on purinergic receptor‑activated Ca²⁺ mobilization and is inhibited by Cl⁻ channel blockers. ATP secretion from poorly coupled cell lines is potentiated 5‑ to 15‑fold by connexin expression, and calcium wave propagation is reduced by purinergic receptor antagonists and Cl⁻ channel blockers but insensitive to gap junction inhibitors, indicating that connexin‑associated signaling results from enhanced ATP release rather than increased intercellular coupling.

Abstract

Forced expression of gap junction proteins, connexins, enables gap junction-deficient cell lines to propagate intercellular calcium waves. Here, we show that ATP secretion from the poorly coupled cell lines, C6 glioma, HeLa, and U373 glioblastoma, is potentiated 5- to 15-fold by connexin expression. ATP release required purinergic receptor-activated intracellular Ca 2+ mobilization and was inhibited by Cl − channel blockers. Calcium wave propagation also was reduced by purinergic receptor antagonists and by Cl − channel blockers but insensitive to gap junction inhibitors. These observations suggest that cell-to-cell signaling associated with connexin expression results from enhanced ATP release and not, as previously believed, from an increase in intercellular coupling.