title: Endogenous arginine-phenylalanine-amide-related peptides alter steady-state desensitization of ASIC1a.
abstract: The acid-sensing ion channels (ASICs) are proton-gated, voltage-insensitive cation channels expressed throughout the nervous system. ASIC1a plays a role in learning, pain, and fear-related behaviors. In addition, activation of ASIC1a during prolonged acidosis following cerebral ischemia induces neuronal death. ASICs undergo steady-state desensitization, a characteristic that limits ASIC1a activity and may play a prominent role in the prevention of ASIC1a-evoked neuronal death. In this study, we found exogenous and endogenous arginine-phenylalanine-amide (RF-amide)-related peptides decreased the pH sensitivity of ASIC1a steady-state desensitization. During conditions that normally induced steady-state desensitization, these peptides profoundly enhanced ASIC1a activity. We also determined that human ASIC1a required more acidic pH to undergo steady-state desensitization compared with mouse ASIC1a. Surprisingly, steady-state desensitization of human ASIC1a was also affected by a greater number of peptides compared with mouse ASIC1a. Mutation of five amino acids in a region of the extracellular domain changed the characteristics of human ASIC1a to those of mouse ASIC1a, suggesting that this region plays a pivotal role in neuropeptide and pH sensitivity of steady-state desensitization. Overall, these experiments lend vital insight into steady-state desensitization of ASIC1a and expand our understanding of the structural determinants of RF-amide-related peptide modulation. Furthermore, our finding that endogenous peptides shift steady-state desensitization suggests that RF-amides could impact the role of ASIC1a in both pain and neuronal damage following stroke and ischemia.
authors.affiliation: Department of Neuroscience, Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Sherwood
authors.forename: Candice C
authors.initials: CC
authors.lastname: Askwith
mesh_terms: D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000235:genetics / Q000378:metabolism; D000577:Amides / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D005239:Fear; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007858:Learning; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D020521:Stroke / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: C568266:ASIC1 protein, human; C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D000577:Amides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D015222:Sodium Channels