Abstract
Type II vestibular hair cells (VHCs II) contain big-conductance Ca2+-dependent K+ channels (BK) and l-type calcium channels. Our previous studies in guinea pig VHCs II indicated that acetylcholine (ACh) evoked the BK current by triggering the influx of Ca2+ ions through l-type Ca2+ channels, which was mediated by M2 muscarinic ACh receptor (mAChRs). Aminoglycoside antibiotics, such as gentamicin (GM), are known to have vestibulotoxicity, including damaging effects on the efferent nerve endings on VHCs II. This study used the whole-cell patch clamp technique to determine whether GM affects the vestibular efferent system at postsynaptic M2-mAChRs or the membrane ion channels. We found that GM could block the ACh-induced BK current and that inhibition was reversible, voltage-independent, and dose-dependent with an IC50 value of 36.3 ± 7.8 μM. Increasing the ACh concentration had little influence on GM blocking effect, but increasing the extracellular Ca2+ concentration ([Ca2+]o) could antagonize it. Moreover, 50 μM GM potently blocked Ca2+ currents activated by (−)-Bay-K8644, but did not block BK currents induced by NS1619. These observations indicate that GM most likely blocks the M2 mAChR-mediated response by competing with Ca2+ at the l-type calcium channel. These results provide insights into the vestibulotoxicity of aminoglycoside antibiotics on mammalian VHCs II.
Highlights
Aminoglycoside antibiotics are commonly used in developing countries due to their powerful broad-spectrum bactericidal ability, inexpensive cost and low allergenicity
Many studies have demonstrated that aminoglycosides, including GM, can block many ion channels, such as voltage-gated calcium channels [4,5,6,7], mechanosensitive ion channels [8,9,10,11,12], and nicotinic ACh receptors [13,14,15]
In the present study, using the whole-cell patch clamp technique, we demonstrated that GM could reversibly block the ACh-induced big-conductance Ca2+-dependent K+ channels (BK) current in guinea pig vestibular hair cells (VHCs) II in a dose-dependent and voltage-independent manner, which indicated that acute
Summary
Aminoglycoside antibiotics are commonly used in developing countries due to their powerful broad-spectrum bactericidal ability, inexpensive cost and low allergenicity. Intratympanic application of gentamicin (GM), an ototoxic aminoglycoside, could be efficacious for treating vertigo in Meniere’s disease because it is more toxic to vestibular hair cells (VHCs) than cochlea hair cells [1,2,3]. Most studies have focused on the molecular mechanism of the hair cell damage by aminoglycosides. It was previously reported that acute GM application can block the Ca2+ channel and the Ca2+-dependent K+ channel in semicircular canal hair cells of the frog [20]. In mammals, it remains poorly understood whether GM could affect the vestibular efferent system and whether GM could block ion channels present on VHCs
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