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Gentamicin blocks ACh-evoked K⁺ current in guinea-pig outer hair cells by impairing Ca²⁺ entry at the cholinergic receptor

Christophe Blanchet, Carlos Eróstegui, Masashi Sugasawa and Didier Dulon

1. Aminoglycoside antibiotics such as gentamicin are known to block the medial olivocochlear efferent system. In order to determine whether this inhibition takes place at the postsynaptic cholinergic receptors in outer hair cells (OHCs), we studied the effects of these polycationic molecules on cholinergic currents evoked in isolated guinea-pig OHCs.

2. The cholinergic response of OHCs involves nicotinic-like receptors (nAChRs) permeable to Ca²⁺ ions that activate nearby Ca²⁺-sensitive K⁺ channels (K_Ca(ACh) channels). The extracellular application of gentamicin and neomycin reversibly blocked ACh-evoked K⁺ current (I_K(ACh)) with IC₅₀ values of 5·5 and 3·2 µM, respectively. The results showed that the blocking mechanism of I_K(ACh) was due to inhibition of Ca²⁺ influx via nAChRs.

3. Our study also provides interesting insights into the functional coupling between nAChRs and K_Ca(ACh) channels in OHCs. By directly recording the cation current flowing through nAChRs (I_n(ACh)) using an intracellular solution containing 10 mM BAPTA, we measured an EC₅₀ near 110 µM for ACh-evoked I_n(ACh). This EC₅₀ for ACh is one order of magnitude higher than that measured indirectly on I_K(ACh). This reveals a rather low affinity of ACh for its receptor but a very efficient coupling between nAChRs and K_Ca(ACh) channels.

4. We also show that a high external Ca²⁺ concentration reverts the gentamicin inhibition of I_K(ACh) and that gentamicin directly alters the cation current flowing through the nAChRs of OHCs. We propose that gentamicin acts as a non-competitive cholinergic blocker by displacing Ca²⁺ from specific binding sites at the nAChRs. This block of the nAChRs at the level of the postsynaptic membrane in OHCs could explain the inhibitory effect of gentamicin reported on the crossed medial olivocochlear efferent system in vivo.

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