Inner ear connexins, intercellular signalling and deafness.

The genes GJB2 and GJB6 respectively encoding transmembrane proteins connexin 26 (C×26) and connexin 30 (C×30) are found within 50 kb of each other in the DFNB1 complex deafness locus on chromosome 13ql2. Up to 50% of all patients with autosomal recessive non-syndromic prelingual deafness in different populations present with mutations or deletions in this locus. C×26 and C×30 are abundantly expressed in the inner ear and, in recent years, have been shown to form hemichannels that release ATP from the endolymphatic surface of supporting and epithelial cells of the organ of Corti (OoC), as well as gap junction (GJ) channels that allow the concomitant intercellular diffusion of Ca2+ mobilizing second messengers. Released ATP in turn activates G-protein coupled P2Y2 and P2Y4 receptors, PLC-dependent generation of IP3, release of Ca2+ from intracellular stores, ensuing in the regenerative propagation of intercellular Ca2+ signals (ICS) across these coupled cells. The range of ICS propagation in the OoC is sensitive to the concentration of extracellular divalent cations and to ectonucleotidase activity. Strictly related oscillations of the intracellular free Ca2+ concentration ([Ca2+]i) in cochlear supporting cells are also evoked by nanomolar concentrations of ATP on the endolymphatic surface of the OoC. ICS and [Ca2+]i oscillations are of great interest in relation to the responses evoked by damaging stimuli delivered to hair cells, and may play a crucial role in development of the OoC and the acquisition of hearing.