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The Journal of neuroscience : the official journal of the Society for Neuroscience
Nov 11, 2009;29 (45): 14371-80.

Dynorphin opioid peptides enhance acid-sensing ion channel 1a activity and acidosis-induced neuronal death.

Thomas W Sherwood, Candice C Askwith
Author Information
  1. Thomas W Sherwood: Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, USA.
PMID: 19906984 DOI: 10.1523/JNEUROSCI.2186-09.2009

Abstract

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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Grants

  1. R01 NS062967/NINDS NIH HHS
  2. R01 NS062967-01/NINDS NIH HHS

MeSH Term

Acid Sensing Ion Channels
Acidosis
Analysis of Variance
Animals
Cell Death
Cells, Cultured
Dynorphins
Hippocampus
Hydrogen-Ion Concentration
Mice
Nerve Tissue Proteins
Neurons
Patch-Clamp Techniques
Peptides
Protons
Receptors, Bradykinin
Receptors, Opioid
Sodium Channels
Spider Venoms
Xenopus laevis

Chemicals

ASIC1 protein, mouse
Acid Sensing Ion Channels
Nerve Tissue Proteins
PcTX1 protein, Psalmopoeus cambridgei
Peptides
Protons
Receptors, Bradykinin
Receptors, Opioid
Sodium Channels
Spider Venoms
Dynorphins
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Word Cloud

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