Stomatin‐domain protein interactions with acid‐sensing ion channels modulate nociceptor mechanosensitivity
Authors: Moshourab Rabih A. , Wetzel Christiane , Martinez‐Salgado Carlos , Lewin Gary R. 
Published: August 2013

Key points
Gene deletion studies revealed that membrane proteins stomatin and STOML3, as well as the acid‐sensing ion channels ASIC2 and ASIC3, regulate mechanosensory transduction.
Both stomatin and STOML3 interact with ASIC proteins and we asked if deletion of two interacting proteins has a more than additive effect on the mechanosensitivity of cutaneous sensory afferents.
A detailed electrophysiological comparison of sensory afferent phenotypes observed in asic3−/−:stomatin−/−, asic3−/−:stoml3−/− and asic2−/−:stomatin−/− mutant mice compared to their respective single gene mutants revealed especially strong effects on the mechanosensitivity of thinly myelinated mechanonociceptors in double mutants.
Deletion of the asic3 gene or pharmacological blockade of this channel decreased adaptation rates specifically in rapidly adapting mechanoreceptors, an effect not exacerbated by deletion of stomatin‐domain genes.
This study reveals that loss of stomatin–ASIC interactions can have profound effects on mechanosensitivity in specific subsets of skin afferents; interfering with such interactions could have potential for treating mechanical pain.
Abstract  Acid‐sensing ion channels (ASICs) and their interaction partners of the stomatin family have all been implicated in sensory transduction. Single gene deletion of asic3, asic2, stomatin, or stoml3 all result in deficits in the mechanosensitivity of distinct cutaneous afferents in the mouse. Here, we generated asic3−/−:stomatin−/−, asic3−/−:stoml3−/− and asic2−/−:stomatin−/− double mutant mice to characterize the functional consequences of stomatin–ASIC protein interactions on sensory afferent mechanosensitivity. The absence of ASIC3 led to a clear increase in mechanosensitivity in rapidly adapting mechanoreceptors (RAMs) and a decrease in the mechanosensitivity in both Aδ‐ and C‐fibre nociceptors. The increased mechanosensitivity of RAMs could be accounted for by a loss of adaptation which could be mimicked by local application of APETx2 a toxin that specifically blocks ASIC3. There is a substantial loss of mechanosensitivity in stoml3−/− mice in which ∼35% of the myelinated fibres lack a mechanosensitive receptive field and this phenotype was found to be identical in asic3−/−:stoml3−/− mutant mice. However, Aδ‐nociceptors showed much reduced mechanosensitivity in asic3−/−:stoml3−/− mutant mice compared to asic3−/− controls. Interestingly, in asic2−/−:stomatin−/− mutant mice many Aδ‐nociceptors completely lost their mechanosensitivity which was not observed in asic2−/− or stomatin−/− mice. Examination of stomatin−/−:stoml3−/− mutant mice indicated that a stomatin/STOML3 interaction is unlikely to account for the greater Aδ‐nociceptor deficits in double mutant mice. A key finding from these studies is that the loss of stomatin or STOML3 in asic3−/− or asic2−/− mutant mice markedly exacerbates deficits in the mechanosensitivity of nociceptors without affecting mechanoreceptor function.