Acid-Sensing Ion Channels Expression, Identity and Role in the Excitability of the Cochlear Afferent Neurons

Abstract

Acid-sensing ion channels (ASICs) are activated by an increase in the extracellular proton concentration. There are four genes (ASIC1-4) that encode six subunits, and they are involved in diverse neuronal functions, such as mechanosensation, learning and memory, nociception, and modulation of retinal function. In this study, we characterize the ASIC currents of spiral ganglion neurons (SGNs). These ASIC currents are primarily carried by Na+, exhibit fast activation and desensitization, display a pH50 of 6.2 and are blocked by amiloride, indicating that these are ASIC currents. The ASIC currents were further characterized using several pharmacological tools. Gadolinium and acetylsalicylic acid reduced these currents, and FMRFamide, zinc (at high concentrations) and N,N,N’,N’–tetrakis-(2-piridilmetil)-ethylenediamine increased them, indicating that functional ASICs are composed of the subunits ASIC1, ASIC2, and ASIC3. Neomycin and streptomycin reduced the desensitization rate of the ASIC current in SGNs, indicating that ASICs may contribute to the ototoxic action of aminoglycosides. RT-PCR of the spiral ganglion revealed significant expression of all ASIC subunits. By immunohistochemistry the expression of the ASIC1a, ASIC2a, ASIC2b, and ASIC3 subunits was detected in SGNs. Although only a few SGNs exhibited action potential firing in response to an acidic stimulus, protons in the extracellular solution modulated SGN activity during sinusoidal stimulation. Our results show that protons modulate the excitability of SGNs via ASICs.

Acid-sensing ion channel 3: An analgesic target

“…In addition to playing a key role in the somatosensory system, ASIC3 is also expressed in certain sensory organs. For example, in mice ASIC3 is expressed in cochlear spiral ganglion neurones and the organ of Corti [140,141], as well as in the vestibular afferent neurones of rat [142]. With regard to the function of ASIC3 in hearing, ASIC3 -/mice have normal hearing at birth, but go on to develop hearing loss (4 months post birth), however, the mechanism for this early onset hearing loss and any potential role of ASIC3 is not fully understood [141].…”

“…This is because aminoglycosides reduce the desensitization rate of the ASIC-like currents in mouse spiral ganglion neurones, i.e. Na + influx is maintained for a longer period, and a known side-effect of these drugs is ototoxicity associated with persistent Na + entry [140].…”

Protons as Messengers of Intercellular Communication in the Nervous System

“…In the rat vestibule, ASIC1b, and 4 were cloned and cDNA amplified ( Gründer et al, 2000 ; Bässler et al, 2001 ). The ASICs have been shown to be expressed both in the rodent vestibular and cochlear afferent neurons ( Mercado et al, 2006 ; González-Garrido et al, 2015 ). Expression of ASIC1a and ASIC2a was found in small vestibular ganglion neurons and afferent fibers in the utricle and crista stroma of the rat.…”

Acid-Sensing Ion Channels as Potential Therapeutic Targets in Neurodegeneration and Neuroinflammation

“…It is worth to note the sustained component of ASIC3 current. In (c), ASIC currents elicited by different pHs in isolated neurons from the rat spiral ganglion [ 11 ]. In (d), every subunit has a typical half-activation pH.…”