title: N-glycosylation of acid-sensing ion channel 1a regulates its trafficking and acidosis-induced spine remodeling.
abstract: Acid-sensing ion channel-1a (ASIC1a) is a potential therapeutic target for multiple neurological diseases. We studied here ASIC1a glycosylation and trafficking, two poorly understood processes pivotal in determining the functional outcome of an ion channel. We found that most ASIC1a in the mouse brain was fully glycosylated. Inhibiting glycosylation with tunicamycin reduced ASIC1a surface trafficking, dendritic targeting, and acid-activated current density. N-glycosylation of the two glycosylation sites, Asn393 and Asn366, has differential effects on ASIC1a biogenesis. Maturation of Asn393 increased ASIC1a surface and dendritic trafficking, pH sensitivity, and current density. In contrast, glycosylation of Asn366 was dispensable for ASIC1a function and may be a rate-limiting step in ASIC1a biogenesis. In addition, we revealed that acidosis reduced the density and length of dendritic spines in a time- and ASIC1a-dependent manner. ASIC1a N366Q, which showed increased glycosylation and dendritic targeting, potentiated acidosis-induced spine loss. Conversely, ASIC1a N393Q, which had diminished dendritic targeting and inhibited ASIC1a current dominant-negatively, had the opposite effect. These data tie N-glycosylation of ASIC1a with its trafficking. More importantly, by revealing a site-specific effect of acidosis on dendritic spines, our findings suggest that these processes have an important role in regulating synaptic plasticity and determining long-term consequences in diseases that generate acidosis.
authors.affiliation: Department of Cell Biology and Neuroscience, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Jing
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Chu
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Jiang
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Collier
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.forename: Peter M
authors.initials: PM
authors.lastname: Snyder
authors.forename: Xiang-Ming
authors.initials: XM
authors.lastname: Zha
mesh_terms: D062565:Acid Sensing Ion Channels; D000138:Acidosis; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001216:Asparagine / Q000235:genetics / Q000378:metabolism; D019921:Biotinylation / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D049229:Dendritic Spines / Q000502:physiology*; D005260:Female; D005998:Glycine / Q000235:genetics; D006031:Glycosylation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D006863:Hydrogen-Ion Concentration; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D009865:Oocytes; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D051381:Rats; D015222:Sodium Channels / Q000172:deficiency / Q000378:metabolism*; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D014981:Xenopus
chemical_list: C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D014415:Tunicamycin; D001216:Asparagine; D005998:Glycine