The DRASIC Cation Channel Contributes to the Detection of Cutaneous Touch and Acid Stimuli in Mice

Abstract

Cation channels in the DEG/ENaC family are proposed to detect cutaneous stimuli in mammals. We localized one such channel, DRASIC, in several different specialized sensory nerve endings of skin, suggesting it might participate in mechanosensation and/or acid-evoked nociception. Disrupting the mouse DRASIC gene altered sensory transduction in specific and distinct ways. Loss of DRASIC increased the sensitivity of mechanoreceptors detecting light touch, but it reduced the sensitivity of a mechanoreceptor responding to noxious pinch and decreased the response of acid- and noxious heat-sensitive nociceptors. The data suggest that DRASIC subunits participate in heteromultimeric channel complexes in sensory neurons. Moreover, in different cellular contexts, DRASIC may respond to mechanical stimuli or to low pH to mediate normal touch and pain sensation.

ASIC3 Channels in Multimodal Sensory Perception

“…The asic3 -/-mice were significantly more sensitive (76), which is consistent with the early report showing increased light-touch response in asic3 -/-mice (45). These data strongly suggest the participation of ASIC3 in touch perception.…”

“…For example, in the isolated skin-nerve preparation, the response to a drop of pH to 5.0 was reduced in C fibers of ASIC3 null animals. The loss of ASIC3 increased the sensitivity of mechanoreceptors to light touch, but it reduced the sensitivity of a mechanoreceptor to respond to a noxious pinch and decreased the responses of acid-and noxious heat-sensitive nociceptors (45). In contrast, Chen et al (51) found an increased sensitivity to thermal, mechanical, and acidic stimuli in ASIC3 knockout mice but detected no alterations in hypersensitivity after capsaicin or carrageenan treatment.…”

“…Price et al (45) showed that disrupting the mouse asic3 gene altered sensory transduction in specific and distinct ways. For example, in the isolated skin-nerve preparation, the response to a drop of pH to 5.0 was reduced in C fibers of ASIC3 null animals.…”

“…Several members of the ENaC/DEG family of ion channels have been proposed to participate in mechanosensation, the most famous being the degenerins in Caenorhabditis elegans, where they play a critical role in touch sensation and proprioception (74). ASIC3 channels are expressed in mechanoreceptors, including specialized cutaneous mechanosensory structures such as Meissner corpuscles, Merkel nerve endings, free nerve endings, and palisades of lanceolate nerve endings surrounding the hair shaft (45). Mice with targeted deletion of ASIC3 were reported to display a subtle increase in normal light touch perception and painful cutaneous mechanical sensitivity (45) (see also the Cutaneous Nociception section above).…”

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…Therapeutic potential-Since activation of ASIC3 has been implicated in various pain processes [46,51,62,63], APETx2 may be a useful analgesic agent in the treatment or prevention of pain in peripheral sensory system. However, its lack of inhibition of sustained ASIC3 current suggests that it may not be effective in suppressing the chronic pain stimuli.…”