RESUMO
Pimozide is a conventional antipsychotic drug largely used in the therapy for schizophrenia and Tourette's syndrome. Pimozide is assumed to inhibit synaptic transmission at the CNS by acting as a dopaminergic D2 receptor antagonist. Moreover, pimozide has been shown to block voltage-gated Ca2+ and K+ channels in different cells. Despite its widespread clinical use, pimozide can cause several adverse effects, including extrapyramidal symptoms and cardiac arrhythmias. Dizziness and loss of balance are among the most common side effects of pimozide. By using the patch-clamp whole-cell technique, we investigated the effect of pimozide [3 µM] on K+ channels expressed by chicken embryo vestibular type-II hair cells. We found that pimozide slightly blocks a transient outward rectifying A-type K+ current but substantially increases a delayed outward rectifying K+ current. The net result was a significant hyperpolarization of type-II hair cells at rest and a strong reduction of their response to depolarizing stimuli. Our findings are consistent with an inhibitory effect of pimozide on the afferent synaptic transmission by type-II hair cells. Moreover, they provide an additional key to understanding the beneficial/collateral pharmacological effects of pimozide. The finding that pimozide can act as a K+ channel opener provides a new perspective for the use of this drug.
RESUMO
Signal transmission by sensory auditory and vestibular hair cells relies upon Ca2+-dependent exocytosis of glutamate. The Ca2+ current in mammalian inner ear hair cells is predominantly carried through Ca V 1.3 voltage-gated Ca2+ channels. Despite this, Ca V 1.3 deficient mice (Ca V 1.3-/- ) are deaf but do not show any obvious vestibular phenotype. Here, we compared the Ca2+ current (I Ca ) in auditory and vestibular hair cells from wild-type and Ca V 1.3-/- mice, to assess whether differences in the size of the residual I Ca could explain, at least in part, the two phenotypes. Using 5 mM extracellular Ca2+ and near-body temperature conditions, we investigated the cochlear primary sensory receptors inner hair cells (IHCs) and both type I and type II hair cells of the semicircular canals. We found that the residual I Ca in both auditory and vestibular hair cells from Ca V 1.3-/- mice was less than 20% (12-19%, depending on the hair cell type and age investigated) compared to controls, indicating a comparable expression of Ca V 1.3 Ca2+ channels in both sensory organs. We also showed that, different from IHCs, type I and type II hair cells from Ca V 1.3-/- mice were able to acquire the adult-like K+ current profile in their basolateral membrane. Intercellular K+ accumulation was still present in Ca V 1.3-/- mice during I K,L activation, suggesting that the K+-based, non-exocytotic, afferent transmission is still functional in these mice. This non-vesicular mechanism might contribute to the apparent normal vestibular functions in Ca V 1.3-/- mice.
