Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death.
Acid-sensing ion channel 1a (ASIC1a) promotes neuronal damage during pathological acidosis. ASIC1a undergoes a process called steady-state desensitization in which incremental pH reductions desensitize the channel and prevent activation when the threshold for acid-dependent activation is reached. We find that dynorphin A and big dynorphin limit steady-state desensitization of ASIC1a and acid-activated currents in cortical neurons. Dynorphin potentiation of ASIC1a activity is independent of opioid or bradykinin receptor activation but is prevented in the presence of PcTx1, a peptide which is known to bind the extracellular domain of ASIC1a. This suggests that dynorphins interact directly with ASIC1a to enhance channel activity. Inducing steady-state desensitization prevents ASIC1a-mediated cell death during prolonged acidosis. This neuroprotection is abolished in the presence of dynorphins. Together, these results define ASIC1a as a new nonopioid target for dynorphin action and suggest that dynorphins enhance neuronal damage following ischemia by preventing steady-state desensitization of ASIC1a.
Sherwood
Thomas W
TW
Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, USA.
Askwith
Candice C
CC
D062565:Acid Sensing Ion Channels; D000138:Acidosis / Q000503:physiopathology*; D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D004399:Dynorphins / Q000378:metabolism*; D006624:Hippocampus / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010455:Peptides; D011522:Protons; D018002:Receptors, Bradykinin / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013111:Spider Venoms / Q000494:pharmacology; D014982:Xenopus laevis
C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D009419:Nerve Tissue Proteins; C413209:PcTX1 protein, Psalmopoeus cambridgei; D010455:Peptides; D011522:Protons; D018002:Receptors, Bradykinin; D011957:Receptors, Opioid; D015222:Sodium Channels; D013111:Spider Venoms; D004399:Dynorphins