Acid-Sensing Ionic Channels in the Rat Vestibular Endorgans and Ganglia

Abstract

Acid-sensing ionic channels (ASICs) are members of the epithelial Na+ channel/degenerin (ENaC/DEG) superfamily. ASICs are widely distributed in the central and peripheral nervous system. They have been implicated in synaptic transmission, pain perception, and the mechanoreception in peripheral tissues. Our objective was to characterize proton-gated currents mediated by ASICs and to determine their immunolocation in the rat vestibular periphery. Voltage clamp of cultured afferent neurons from P7 to P10 rats showed a proton-gated current with rapid activation and complete desensitization, which was carried almost exclusively by sodium ions. The current response to protons (H+) has a pH0.5 of 6.2. This current was reversibly decreased by amiloride, gadolinium, lead, acetylsalicylic acid, and enhanced by FMRFamide and zinc, and negatively modulated by raising the extracellular calcium concentration. Functional expression of the current was correlated with smaller-capacitance neurons. Acidification of the extracellular pH generated action potentials in vestibular neurons, suggesting a functional role of ASICs in their excitability. Immunoreactivity to ASIC1a and ASIC2a subunits was found in small vestibular ganglion neurons and afferent fibers that run throughout the macula utricle and crista stroma. ASIC2b, ASIC3, and ASIC4 were expressed to a lesser degree in vestibular ganglion neurons. The ASIC1b subunit was not detected in the vestibular endorgans. No acid-pH-sensitive currents or ASIC immunoreactivity was found in hair cells. Our results indicate that proton-gated current is carried through ASICs and that ionic current activated by H+ contributes to shape the vestibular afferent neurons' response to its synaptic input.

The Aminoglycosides Modulate the Acid-Sensing Ionic Channel Currents in Dorsal Root Ganglion Neurons from the Rat

“…The side effects of clinical use of AGs include nausea, vertigo, and paresthesia, among others. These coincide with the demonstration that the vestibular system expresses ASICs that may participate in the afferent neuron excitability (Mercado et al, 2006;Vega et al, 2009), and also that paresthesia may be due to alterations in the excitability of DRG neurons. Other side effects are most probably due to interaction of AGs with targets not related to ASICs, such as inhibition of sodium and calcium currents and with reactive oxygen species generation (Talaska and Schacht, 2007).…”

“…The AGs were freshly prepared before the experiments, and 10 M capsazepine (Sigma-Aldrich) was added in all the experiments to avoid the potential activation of the TRPV1 channels present in DRG neurons (Leffler et al, 2006;Mercado et al, 2006). Because all of the AGs used were sulfate salts, additional controls using 90 M Na 2 SO 4 (which is the sulfate concentration in 30 M streptomycin) were done to define whether the sulfate by itself had any effect on the acidactivated currents.…”

“…In the past decade, the ASICs have gained importance because of their participation in various physiological and physiopathological processes, such as nociception, memory and learning, intercellular communication, development, epilepsy, multiple sclerosis, excitotoxicity, and neoplastic processes (Mercado et al, 2006;Wemmie et al, 2006;Lingueglia, 2007;Xiong et al, 2008). This has made the finding of pharmacological tools capable of altering the ASIC function of special relevance, because they may be used as potential therapeutic agents and may also contribute to a better understanding of ASIC physiology.…”

Ion channels in mammalian vestibular afferents may set regularity of firing

“…Dissociated vestibular somata have been studied with the whole-cell patch method by Desmadryl, Chabbert and colleagues (Autret et al, 2005;Chabbert et al, 1997;Chabbert et al, 2001a;Chabbert et al, 2001b;Desmadryl et al, 1997) and by Soto, Vega and colleagues (Limón et al, 2005;Mercado, 2006). Whole-cell patch recordings have also been made from neurons cultured in semi-intact ganglia (Risner and Holt, 2006).…”

“…Acid-sensing conductances of the DEG/ENaC family are particularly large in small vestibular ganglion somata, where they contribute to spiking evoked by superfusion with acidic solutions (Mercado, 2006). ASIC channels are also found in spiral ganglion neurons (Peng et al, 2004) and DRG neurons (Benson et al, 2002).…”