The metabotropic glutamate receptors of the semicircular canals
Description
Enzymatically isolated SCC hair cells are immunoreactive for both mGluR1a and mGluR5, Furthermore, afferent discharge rate of the frog SCC is increased by application of the group I-selective agonist DHPG (300uM) and the mGluR5-selective agonist CHPG (300uM). These responses are reversibly antagonized by the competitive group I mGluR-selective antagonist (S)-4-CPG (1mM). The response of the SCC to CHPG (300uM) is also blocked by the noncompetitive mGluR5-selective antagonist MPEP-HCI (1mM). The non-competitive mGluR5 antagonist MPEP-HCl dose-dependently reduces mechanically-evoked facilitation of afferent discharge rate (IC50: 136uM), while having no effect on tonic, unstimulated afferent discharge. The response of the SCC to DHPG (300uM) is inhibited by the PLC inhibitor U-73122 (IC50: 33uM), the SERCA inhibitor thapsigargin (IC50: 1uM), ryanodine (IC50: 98uM), an antagonist of the intracellular receptor which mediates CICR, nimodipine (10uM), an L-type VDCC-selective blocker, Co++ (2mM), a non-selective VDCC blocker, and xestospongin C (IC50: 25nM), an IP3 receptor antagonist. Caffeine, at a concentration (5mM) which sensitizes ryanodine receptors to Ca++, increases the mean amplitude (34.6+/-13,4%) and duration (453+/-169,8%; n = 4) of the response of the SCC to DHPG, while 50mM caffeine, known to deplete the ryanodine/caffeine-sensitive intracellular Ca++ reservoir, eliminates this response. The cyclic-ADP ribose antagonist 8-Br-cyclic ADP ribose (1--10uM), and the PKC inhibitor bisindolylmaleimide I-HCl (10--100uM) have no effect on the response of the SCC to DHPG (300uM). Blockade of transmitter release via Ca++-depleted (100uM), Mg++-enriched (10mM), artificial perilymph eliminates the response of the SCC to DHPG, while the afferent response to AMPA (30uM) is unchanged. Preapplication of DHPG (300uM; 60 sec.) under low Ca++/high Mg++ conditions had no effect on the response of the SCC to AMPA (30uM). These findings suggest that, in the SCC: (1) VHCs express both mGluRla and mGluR5. (2) Group I mGluRs on VHCs are selectively activated by mechanically-evoked release of transmitter. This activation leads to positive feedback on evoked transmitter release. (3) Release of Ca++ from IP3-sensitive intracellular stores, triggered by the activation of PLC and augmented by subsequent release from ryanodine-sensitive stores, may be associated with the increase in transmitter release mediated by activation of group I mGluRs on VHCs