Gap junctional hemichannel-mediated ATP release and hearing controls in the inner ear.
Connexin gap junctions play an important role in hearing function, but the mechanism by which this contribution occurs is unknown. Connexins in the cochlea are expressed only in supporting cells; no connexin expression occurs in auditory sensory hair cells. A gap junctional channel is formed by two hemichannels. Here, we show that connexin hemichannels in the cochlea can release ATP at levels that account for the submicromolar concentrations measured in the cochlear fluids in vivo. The release could be increased 3- to 5-fold by a reduction of extracellular Ca2+ or an increase in membrane stress, and blocked by gap junctional blockers. We also demonstrated that extracellular ATP at submicromolar levels apparently affected outer hair cell (OHC) electromotility, which is an active cochlear amplifier determining cochlear sensitivity to sound stimulation in mammals. ATP reduced OHC electromotility and the slope factor of the voltage dependence and shifted the operating point to reduce the active amplifier gain. ATP also reduced the generation of distortion products. Immunofluorescent staining showed that purinergic receptors P2x2 and P2x7 were distributed on the OHC surface. Blockage of P2 receptors eliminated the effect of ATP on the OHC electromotility. The data revealed that there is a hemichannel-mediated, purinergic intercellular signaling pathway between supporting cells and hair cells in the cochlea to control hearing sensitivity. The data also demonstrated a potential source of ATP in the cochlea.
Zhao
Hong-Bo
HB
Department of Surgery-Otolaryngology, University of Kentucky Medical Center, Lexington, KY 40536-0293, USA. hzhao2@uky.edu
Yu
Ning
N
Fleming
Carrie R
CR
D000255:Adenosine Triphosphate / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017630:Connexins / Q000378:metabolism; D007758:Ear, Inner / Q000378:metabolism* / Q000502:physiology*; D017629:Gap Junctions / Q000378:metabolism*; D006168:Guinea Pigs; D006309:Hearing / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000378:metabolism
D017630:Connexins; D018048:Receptors, Purinergic P2; D000255:Adenosine Triphosphate; D002118:Calcium