title: Stomatin-domain protein interactions with acid-sensing ion channels modulate nociceptor mechanosensitivity.
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.
authors: G. R. Lewin: Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, D-13125, Berlin, Germany. glewin@mdc-berlin.de.
authors: Rabih A
authors: RA
authors: Moshourab
authors: Christiane
authors: C
authors: Wetzel
authors: Carlos
authors: C
authors: Martinez-Salgado
authors: Gary R
authors: GR
authors: Lewin
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D008465:Mechanoreceptors / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009475:Neurons, Afferent / Q000378:metabolism / Q000502:physiology; D009619:Nociceptors / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000502:physiology
chemical_list: D062565:Acid Sensing Ion Channels; D001798:Blood Proteins; C488964:Stom protein, mouse; D008565:Membrane Proteins
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