ASIC2 subunits target acid-sensing ion channels to the synapse via an association with PSD-95.
Acid-sensing ion channel-1a (ASIC1a) mediates H(+)-gated current to influence normal brain physiology and impact several models of disease. Although ASIC2 subunits are widely expressed in brain and modulate ASIC1a current, their function remains poorly understood. We identified ASIC2a in dendrites, dendritic spines, and brain synaptosomes. This localization largely relied on ASIC2a binding to PSD-95 and matched that of ASIC1a, which does not coimmunoprecipitate with PSD-95. We found that ASIC2 and ASIC1a associated in brain, and through its interaction with PSD-95, ASIC2 increased ASIC1a localization in dendritic spines. Consistent with earlier work showing that acidic pH elevated spine [Ca(2+)](i) by activating ASIC1a, loss of ASIC2 decreased the percentage of spines responding to acid. Moreover, like a reduction of ASIC1a, the number of spine synapses fell in ASIC2(-/-) neurons. These results indicate that ASIC2 facilitates ASIC1a localization and function in dendritic spines and suggest that the two subunits work in concert to regulate neuronal function.
Zha
Xiang-ming
XM
Howard Hughes Medical Institute, Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Costa
Vivian
V
Harding
Anne Marie S
AM
Reznikov
Leah
L
Benson
Christopher J
CJ
Welsh
Michael J
MJ
D062565:Acid Sensing Ion Channels; D000143:Acids / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002522:Chlorocebus aethiops; D049229:Dendritic Spines / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000378:metabolism; D051528:Guanylate Kinases; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation / Q000379:methods; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000502:physiology*; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000172:deficiency; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D021122:Protein Subunits / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D015222:Sodium Channels / Q000737:chemistry* / Q000172:deficiency; D013569:Synapses / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism; D014162:Transfection / Q000379:methods
C568267:ASIC1 protein, mouse; C568265:ASIC2 protein, mouse; D062565:Acid Sensing Ion Channels; D000143:Acids; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D007473:Ion Channels; D008164:Luminescent Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D018091:Receptors, AMPA; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; D051528:Guanylate Kinases; C104722:glutamate receptor ionotropic, AMPA 2; D002118:Calcium