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The Journal of Neuroscience, November 11, 2009, 29(45):14371-14380; doi:10.1523/JNEUROSCI.2186-09.2009

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 Previous Article

Cellular/Molecular
Dynorphin Opioid Peptides Enhance Acid-Sensing Ion Channel 1a Activity and Acidosis-Induced Neuronal Death

Thomas W. Sherwood and Candice C. Askwith

Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210

Correspondence should be addressed to Candice C. Askwith, 4197 Graves Hall, 333 West 10th Avenue, Department of Neuroscience, The Ohio State University, Columbus, OH 43210. Email: Askwith.1{at}osu.edu

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.

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Received May 6, 2009; revised Oct. 2, 2009; accepted Oct. 10, 2009.

Correspondence should be addressed to Candice C. Askwith, 4197 Graves Hall, 333 West 10th Avenue, Department of Neuroscience, The Ohio State University, Columbus, OH 43210. Email: Askwith.1{at}osu.edu

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