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

Abstract

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.

• calcium
• gap junction
• hearing loss
• hemichannel
• IP3
• intercellular communication