Vestibular-afferent neurons (VANs) transmit information about linear and angular accelerations during head movements from vestibular end organs to vestibular nuclei. In situ, these neurons show heterogeneous discharge patterns that may be produced by differences in their intrinsic properties. However, little is known about the ionic currents underlying their different firing patterns. Using the whole cell patch-clamp technique, we analyzed the expression of Ca(2+) and Ca(2+)-activated K(+) currents (I(KCa)) in primary cultured neurons isolated from young rats (p7-p10). We found two overlapping subpopulations of VANs classified according to low-threshold Ca(2+)-current [low-voltage-activated (LVA)] expression; LVA (-) neurons, formed by small cells, and LVA (+) neurons composed of medium to large cells. The I(KCa) in both cell-groups was carried through channels of high (BK), intermediate (IK), and low conductance (SK), besides a resistant channel to classical blockers (IR). BK was expressed preferentially in LVA (+) cells, whereas IR expression was preferentially in LVA (-) cells. No correlation between SK and IK expression with the soma size was found. Current-clamp experiments showed that BK participates in the adaptation of discharge and in the duration of the action potential, whereas SK and IK did not show a significant contribution to electrical discharge of cultured VANs. However, because of the low number of VANs in culture with repetitive firing it is difficult to interpret our results in terms of discharge patterns. Our results demonstrate that vestibular-afferent neurons possess different Ca(2+)-activated K(+) (K(Ca)) channels and that their expression, heterogeneous among the cells, would contribute to explain some of the differences in the electrical-firing properties of these neurons.

This work reviews the neuropharmacology of the vestibular system, with an emphasis on the mechanism of action of drugs used in the treatment of vestibular disorders. Otolaryngologists are confronted with a rapidly changing field in which advances in the knowledge of ionic channel function and synaptic transmission mechanisms have led to the development of new scientific models for the understanding of vestibular dysfunction and its management. In particular, there have been recent advances in our knowledge of the fundamental mechanisms of vestibular system function and drug mechanisms of action. In this work, drugs acting on vestibular system have been grouped into two main categories according to their primary mechanisms of action: those with effects on neurotransmitters and neuromodulator receptors and those that act on voltage-gated ion channels. Particular attention is given in this review to drugs that may provide additional insight into the pathophysiology of vestibular diseases. A critical review of the pharmacology and highlights of the major advances are discussed in each case.

Acid-sensing ion channels (ASICs) are a family of proton-sensing channels that are voltage insensitive, cation selective (mostly permeable to Na+), and nonspecifically blocked by amiloride. Derived from 5 genes (ACCN1–5), 7 subunits have been identified, 1a, 1b, 2a, 2b, 3, 4, and 5, that are widely expressed in the peripheral and central nervous system as well as other tissues. Over the years, different studies have shown that activation of these channels is linked to various physiological and pathological processes, such as memory, learning, fear, anxiety, ischemia, and multiple sclerosis to name a few, so their potential as therapeutic targets is increasing. This review focuses on recent advances that have helped us to better understand the role played by ASICs in different pathologies related to neurodegenerative diseases, inflammatory processes, and pain.

Properties, developmental regulation, and cAMP modulation of the hyperpolarization-activated current (I(h)) were investigated by the whole cell patch-clamp technique in vestibular ganglion neurons of the rat at two postnatal stages (P7-10 and P25-28). In addition, by RT-PCR and immunohistochemistry the identity and distribution of hyperpolarization-activated and cyclic nucleotide-gated channel (HCN) isoforms that generate I(h) were investigated. I(h) current density was larger in P25-28 than P7-10 rats, increasing 410% for small cells (<30 pF) and 200% for larger cells (>30 pF). The half-maximum activation voltage (V(1/2)) of I(h) was -102 mV in P7-10 rats and in P25-28 rats shifted 7 mV toward positive voltages. At both ages, intracellular cAMP increased I(h) current density, decreased its activation time constant (τ), and resulted in a rightward shift of V(1/2) by 9 mV. Perfusion of 8-BrcAMP increased I(h) amplitude and speed up its activation kinetics. I(h) was blocked by Cs(+), zatebradine, and ZD7288. As expected, these drugs also reduced the voltage sag caused with hyperpolarizing pulses and prevented the postpulse action potential generation without changes in the resting potential. RT-PCR analysis showed that HCN1 and HCN2 subunits were predominantly amplified in vestibular ganglia and end organs and HCN3 and HCN4 to a lesser extent. Immunohistochemistry showed that the four HCN subunits were differentially expressed (HCN1 > HCN2 > HCN3 ≥ HCN4) in ganglion slices and in cultured neurons at both P7-10 and P25-28 stages. Developmental changes shifted V(1/2) of I(h) closer to the resting membrane potential, increasing its functional role. Modulation of I(h) by cAMP-mediated signaling pathway constitutes a potentially relevant control mechanism for the modulation of afferent neuron discharge.

Almanza A, Navarrete F, Vega R, Soto E. Modulation of voltagegated Ca 2ϩ current in vestibular hair cells by nitric oxide. J Neurophysiol 97: 1188Neurophysiol 97: -1195Neurophysiol 97: , 2007. First published December 20, 2006; doi:10.1152/jn.00849.2006. The structural elements of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathway have been described in the vestibular peripheral system. However, the functions of NO in the vestibular endorgans are still not clear. We evaluated the action of NO on the Ca 2ϩ currents in hair cells isolated from the semicircular canal crista ampullaris of the rat (P14 -P18) by using the whole cell and perforated-cell patch-clamp technique. The NO donors 3-morpholinosydnonimine (SIN-1), sodium nitroprusside (SNP), and ( In the presence of Nethylmaleimide (NEM), a sulfhydryl alkylating agent that prevents the S-nitrosylation reaction, the SNP effect on the Ca 2ϩ current was significantly diminished. These results demonstrated that NO inhibits in a voltage-independent manner the voltage-activated Ca 2ϩ current in rat vestibular hair cells by the activation of a cGMP-signaling pathway and through a direct action on the channel protein by a Snitrosylation reaction. The inhibition of the Ca 2ϩ current by NO may contribute to the regulation of the intracellular Ca 2ϩ concentration and hair-cell synaptic transmission.