RT Journal Article
SR Electronic
T1 Dynorphin Opioid Peptides Enhance Acid-Sensing Ion Channel 1a Activity and Acidosis-Induced Neuronal Death
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 14371
OP 14380
DO 10.1523/JNEUROSCI.2186-09.2009
VO 29
IS 45
A1 Thomas W. Sherwood
A1 Candice C. Askwith
YR 2009
UL http://www.jneurosci.org/content/29/45/14371.abstract
AB 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.