title: Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines.
abstract: Extracellular proton concentrations in the brain may be an important signal for neuron function. Proton concentrations change both acutely when synaptic vesicles release their acidic contents into the synaptic cleft and chronically during ischemia and seizures. However, the brain receptors that detect protons and their physiologic importance remain uncertain. Using organotypic hippocampal slices and biolistic transfection, we found the acid-sensing ion channel 1a (ASIC1a), localized in dendritic spines where it functioned as a proton receptor. ASIC1a also affected the density of spines, the postsynaptic site of most excitatory synapses. Decreasing ASIC1a reduced the number of spines, whereas overexpressing ASIC1a had the opposite effect. Ca(2+)-mediated Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) signaling was probably responsible, because acid evoked an ASIC1a-dependent elevation of spine intracellular Ca(2+) concentration, and reducing or increasing ASIC1a levels caused parallel changes in CaMKII phosphorylation in vivo. Moreover, inhibiting CaMKII prevented ASIC1a from increasing spine density. These data indicate that ASIC1a functions as a postsynaptic proton receptor that influences intracellular Ca(2+) concentration and CaMKII phosphorylation and thereby the density of dendritic spines. The results provide insight into how protons influence brain function and how they may contribute to pathophysiology.
authors.affiliation: Howard Hughes Medical Institute, and Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Xiang-ming
authors.initials: XM
authors.lastname: Zha
authors.forename: John A
authors.initials: JA
authors.lastname: Wemmie
authors.forename: Steven H
authors.initials: SH
authors.lastname: Green
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welsh
mesh_terms: D062565:Acid Sensing Ion Channels; D000143:Acids / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D011522:Protons; D015222:Sodium Channels / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D000143:Acids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010455:Peptides; D011522:Protons; D015222:Sodium Channels; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium