title: Ryanodine receptors and BK channels act as a presynaptic depressor of neurotransmission in cochlear inner hair cells.
abstract: Ryanodine receptors (RyRs) are known to contribute to the regulation of free cytosolic calcium concentration. This family of intracellular calcium channels plays a significant role in calcium-induced-calcium-release (CICR), and have been implicated in calcium-dependent processes requiring exquisite spatio-temporal regulation. In order to characterize the importance of these intracellular calcium channels in cochlear physiology, we perfused the guinea pig cochlea with antagonistic concentrations of ryanodine. The distortion products of the cochlear microphonic and the compound action potential of the auditory nerve were reversibly inhibited by ryanodine (IC(50)=27.3 microm, Hill coefficient=1.9), indicating an action at the cochlear amplifier. Single auditory nerve fibre recordings showed that ryanodine slightly increased spontaneous firing rates by 22%, suggesting an excitatory effect of ryanodine. This paradoxical effect could be explained by an inhibitory action of ryanodine on presynaptic BK channels of inner hair cells (IHC). Indeed, perfusing iberiotoxin also increased the spontaneous firing activity of the auditory nerve fibres. Furthermore, whole-cell patch-clamp recordings demonstrated that ryanodine inhibits BK currents at the IHC level. Conversely, immunohistochemistry demonstrated a strong expression of RyR in IHCs and, more particularly, below the cuticular plate where membranous BK channels are highly expressed. Overall, the study demonstrated a key role for RyR and CICR in signal transduction at the IHCs. We therefore propose that coupled RyR--BK channels act to suppress the fast neurotransmission in IHCs.
authors.affiliation: Laboratoire de Biologie Cellulaire et Moléculaire de l'Audition, EA 3665 Université Victor Segalen Bordeaux 2, CHU Hôpital Pellegrin, 33076 Bordeaux, France.
authors.forename: Maryline
authors.initials: M
authors.lastname: Beurg
authors.forename: Aziz
authors.initials: A
authors.lastname: Hafidi
authors.forename: Liam J
authors.initials: LJ
authors.lastname: Skinner
authors.forename: Jérome
authors.initials: J
authors.lastname: Ruel
authors.forename: Régis
authors.initials: R
authors.lastname: Nouvian
authors.forename: Morgana
authors.initials: M
authors.lastname: Henaff
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Puel
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Aran
authors.forename: Didier
authors.initials: D
authors.lastname: Dulon
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D003051:Cochlea / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005072:Evoked Potentials, Auditory / Q000502:physiology; D006168:Guinea Pigs; D006199:Hair Cells, Auditory, Inner / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008959:Models, Neurological; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000494:pharmacology; D012433:Ryanodine / Q000494:pharmacology; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D010455:Peptides; D019837:Ryanodine Receptor Calcium Release Channel; D012433:Ryanodine; C064719:iberiotoxin