Hemichannel-Mediated Inositol 1,4,5-Trisphosphate (IP3) Release in the Cochlea: A Novel Mechanism of IP3 Intercellular Signaling

Inositol 1,4,5-trisphosphate (IP3) is an important second messenger that can trigger a Ca2+ wave prolongated between cells. This intercellular signaling was found defective in some gap junction connexin deafness mutants. In this study, the mechanism underlying IP3 intercellular signaling in the cochlea was investigated. A gap junction channel is composed of two hemichannels. By using a fluorescence polarization technique to measure IP3 concentration, the authors found that IP3 could be released by gap junction hemichannels in the cochlea. The IP3 release was increased about three- to fivefold by the reduction of extracellular Ca2+ concentration or by mechanical stress. This incremental release could be blocked by gap junction blockers but not eliminated by a purinergic P2x receptor antagonist and verapamil, which is a selective P-glycoprotein inhibitor inhibiting the ATP-binding cassette transporters. The authors also found that IP3 receptors were extensively expressed in the cochlear sensory epithelium, including on the cell surface. Extracellular application of IP3 could trigger cellular Ca2+ elevation. This Ca2+ elevation was eliminated by the gap junction hemichannel blocker. These data reveal that IP3 can pass through hemichannels acting as an extracellular mediator to participate in intercellular signaling. This hemichannel-mediated extracellular pathway may play an important role in long-distance intercellular communication in the cochlea, given that IP3 only has a short lifetime in the cytoplasm.