Simultaneous Disruption of Mouse ASIC1a, ASIC2 and ASIC3 Genes Enhances Cutaneous Mechanosensitivity

Abstract

Three observations have suggested that acid-sensing ion channels (ASICs) might be mammalian cutaneous mechanoreceptors; they are structurally related to Caenorhabditis elegans mechanoreceptors, they are localized in specialized cutaneous mechanosensory structures, and mechanical displacement generates an ASIC-dependent depolarization in some neurons. However, previous studies of mice bearing a single disrupted ASIC gene showed only subtle or no alterations in cutaneous mechanosensitivity. Because functional redundancy of ASIC subunits might explain limited phenotypic alterations, we hypothesized that disrupting multiple ASIC genes would markedly impair cutaneous mechanosensation. We found the opposite. In behavioral studies, mice with simultaneous disruptions of ASIC1a, -2 and -3 genes (triple-knockouts, TKOs) showed increased paw withdrawal frequencies when mechanically stimulated with von Frey filaments. Moreover, in single-fiber nerve recordings of cutaneous afferents, mechanical stimulation generated enhanced activity in A-mechanonociceptors of ASIC TKOs compared to wild-type mice. Responses of all other fiber types did not differ between the two genotypes. These data indicate that ASIC subunits influence cutaneous mechanosensitivity. However, it is unlikely that ASICs directly transduce mechanical stimuli. We speculate that physical and/or functional association of ASICs with other components of the mechanosensory transduction apparatus contributes to normal cutaneous mechanosensation.

Effect of Deep Tissue Incision on pH Responses of Afferent Fibers and Dorsal Root Ganglia Innervating Muscle

“…27 ASICs also contribute to mechanosensation. 28-32 In the periphery, loss of ASICs has been attributed to deficits in hearing 33 and reduced visceral sensation 29 but increased cutaneous mechanoreceptor function. 28 …”

Acid-sensing ion channels in pain and disease

“…However, early results were mixed. For example, ASIC3-knockout mice and mice with simultaneous disruption of ASIC1A, ASIC2 and ASIC3 showed increased pain-related behaviours 55,56 . By contrast, pharmacological blockade using the sea anemone peptide APETx2 and genetic knockdown of Asic3 decreased pain-related behaviours 57 .…”

International Union of Basic and Clinical Pharmacology. XCI. Structure, Function, and Pharmacology of Acid-Sensing Ion Channels and the Epithelial Na+Channel

“…Surprisingly, two studies showed that mice in which all ASIC currents were suppressed displayed increased pain behavior (Mogil et al, 2005;Kang et al, 2012). Mice overexpressing a dominant-negative mutant ASIC3 subunit were more sensitive than wild-type controls to mechanical pain and chemical/inflammatory pain and developed stronger mechanical hypersensitivity after inflammation (Mogil et al, 2005).…”

“…Mice overexpressing a dominant-negative mutant ASIC3 subunit were more sensitive than wild-type controls to mechanical pain and chemical/inflammatory pain and developed stronger mechanical hypersensitivity after inflammation (Mogil et al, 2005). Triple knockout mice, in which the ASIC1, ASIC2, and ASIC3 genes were simultaneously disrupted, showed an increased behavioral sensitivity to mechanical stimuli and an increased mechanosensitivity of A-mechanonociceptors (Kang et al, 2012). This indicates that the role of ASICs in nociception is still not fully understood despite many important findings.…”