Stomatin modulates gating of acid-sensing ion channels.
Acid-sensing ion channels (ASICs) are H(+)-gated members of the degenerin/epithelial Na(+) channel (DEG/ENaC) family in vertebrate neurons. Several ASICs are expressed in sensory neurons, where they play a role in responses to nociceptive, taste, and mechanical stimuli; others are expressed in central neurons, where they participate in synaptic plasticity and some forms of learning. Stomatin is an integral membrane protein found in lipid/protein-rich microdomains, and it is believed to regulate the function of ion channels and transporters. In Caenorhabditis elegans, stomatin homologs interact with DEG/ENaC channels, which together are necessary for normal mechanosensation in the worm. Therefore, we asked whether stomatin interacts with and modulates the function of ASICs. We found that stomatin co-immunoprecipitated and co-localized with ASIC proteins in heterologous cells. Moreover, stomatin altered the function of ASIC channels. Stomatin potently reduced acid-evoked currents generated by ASIC3 without changing steady state protein levels or the amount of ASIC3 expressed at the cell surface. In contrast, stomatin accelerated the desensitization rate of ASIC2 and heteromeric ASICs, whereas current amplitude was unaffected. These data suggest that stomatin binds to and alters the gating of ASICs. Our findings indicate that modulation of DEG/ENaC channels by stomatin-like proteins is evolutionarily conserved and may have important implications for mammalian nociception and mechanosensation.
Department of Internal Medicine, University of Iowa College of Medicine, 200 Hawkins Dr., Iowa City, IA 52242, USA.
Margaret P
MP
Price
Robert J
RJ
Thompson
Jayasheel O
JO
Eshcol
John A
JA
Wemmie
Christopher J
CJ
Benson
D062565:Acid Sensing Ion Channels; D000818:Animals; D019921:Biotinylation; D001798:Blood Proteins / Q000502:physiology*; D016466:CHO Cells; D019556:COS Cells; D017173:Caenorhabditis elegans; D002462:Cell Membrane / Q000378:metabolism; D017124:Conserved Sequence; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D019143:Evolution, Molecular; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000737:chemistry* / Q000502:physiology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009419:Nerve Tissue Proteins / Q000737:chemistry*; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D015222:Sodium Channels / Q000737:chemistry*; D013997:Time Factors; D014162:Transfection
C568265:ASIC2 protein, mouse; D062565:Acid Sensing Ion Channels; D001798:Blood Proteins; D018076:DNA, Complementary; C488964:Stom protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D015222:Sodium Channels