Suppression of delayed rectifier K channels by gentamicin induces membrane hyperexcitability through JNK and PKA signaling pathways in vestibular ganglion neurons.

Aminoglycoside antibiotics, such as gentamicin, are known to have vestibulotoxic effects, including ataxia and disequilibrium. To date, however, the underlying cellular and molecular mechanisms are still unclear. In this study, we determined the role of gentamicin in regulating the sustained delayed rectifier K current (I) and membrane excitability in vestibular ganglion (VG) neurons in mice. Our results showed that the application of gentamicin to VG neurons decreased the I in a concentration-dependent manner, while the transient outward A-type K current (I) remained unaffected. The decrease in I induced by gentamicin was independent of G-protein activity and led to a hyperpolarizing shift of the inactivation V. The analysis of phospho-c-Jun N-terminal kinase (p-JNK) revealed that gentamicin significantly stimulated JNK, while p-ERK and p-p38 remained unaffected. Blocking Kv1 channels with α-dendrotoxin or pretreating VG neurons with the JNK inhibitor II abrogated the gentamicin-induced decrease in I. Antagonism of JNK signaling attenuated the gentamicin-induced stimulation of PKA activity, whereas PKA inhibition prevented the I response induced by gentamicin. Moreover, gentamicin significantly increased the number of action potentials fired in both phasic and tonic firing type neurons; pretreating VG neurons with the JNK inhibitor II and the blockade of the I abolished this effect. Taken together, our results demonstrate that gentamicin decreases the I through a G-protein-independent but JNK and PKA-mediated signaling pathways. This gentamicin-induced I response mediates VG neuronal hyperexcitability and might contribute to its pharmacological vestibular effects.