Acid-Sensing Ion Channel 2 Contributes a Major Component to Acid-Evoked Excitatory Responses in Spiral Ganglion Neurons and Plays a Role in Noise Susceptibility of Mice

Abstract

Ion channels in the degenerin-epithelial sodium channel (DEG-ENaC) family perform diverse functions, including mechanosensation. Here we explored the role of the vertebrate DEG-ENaC protein, acid-sensing ion channel 2 (ASIC2), in auditory transduction. Contributions of ASIC2 to hearing were examined by comparing hearing threshold and noise sensitivity of wild-type and ASIC2 null mice. ASIC2 null mice showed no significant hearing loss, indicating that the ASIC2 was not directly involved in the mechanotransduction of the mammalian cochlea. However, we found that (1) ASIC2 was present in the spiral ganglion (SG) neurons in the adult cochlea and that externally applied protons induced amiloride-sensitive sodium currents and action potentials in SG neurons in vitro, (2) proton-induced responses were greatly reduced in SG neurons obtained from ASIC2 null mice, indicating that activations of ASIC2 contributed a major portion of the proton-induced excitatory response in SG neurons, and (3) ASIC2 null mice were considerably more resistant to noiseinduced temporary, but not permanent, threshold shifts. Together, these data suggest that ASIC2 contributes to suprathreshold functions of the cochlea. The presence of ASIC2 in SG neurons could provide sensors to directly convert local acidosis to excitatory responses, therefore offering a cellular mechanism linking hearing losses caused by many enigmatic causes (e.g., ischemia or inflammation of the inner ear) to excitotoxicity.

The acid-sensing ion channel 2 (ASIC2) of ciliated cells in the developing rat nasal septum

“…For the nervous systems, differences in the localization of ASIC subtypes have been reported: all ASIC subtypes were observed in the peripheral nervous system (PNS) while ASIC1a, 2a and 2b were found in the spinal cord and ASIC1a, 2a and 4 in the brain (Price et al, 1996;Chen et al, 1998;Babinski et al, 2000;Peng et al, 2004;Lingueglia, 2007). We also reported that ASIC2 expression was detected in the ciliated cells of the rat trachea although the subtypes were not clarified in our previous study (Kikuchi et al, 2008).…”

Ion Channel Gene Expression in the Inner Ear

“…This K + selective leak channel passes larger outward than inward currents due to open channel rectification (Plant et al 2005). TWIK-1 (KCNK1) and TWIK-2 (KCNK6) were found previously in the rodent inner ear using RT-PCR and immunolocalized to the strial and dark cells of the cochlea and vestibule, respectively (Nicolas et al 2003;Mhatre et al 2004).…”

“…TRPV1 channel not revealed by high-throughput experiments was identified previously by PCR (Kitahara et al 2005). TRPV2 was identified recently by MPSS analysis of mouse inner ear (Peters et al 2007). …”

“…However, there was no mutation of ACCN3 in a family with DFNB13 hearing loss, despite ACCN3 mapping to the same chromosomal region as DFNB13. Deletions of other members, such as Asic2 (ACCN2), do not produce deafness in mice; although this mutation decreases spiral ganglion responses and susceptibility to noise (Peng et al 2004). In comparison, Asic1b (ACCN1) channels are localized to the base of the stereocilia, but its function in the inner ear is not known (Ugawa et al 2006).…”

Restoration of connexin26 protein level in the cochlea completely rescues hearing in a mouse model of human connexin30-linked deafness

“…Details of the ABR testing protocol are given in our previous publication (23). Briefly, mice were anesthetized with ketamine (80 mg/kg) and xylazine (10 mg/kg).…”