Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a

Chassagnon, Irene R., McCarthy, Claudia A., Chin, Yanni K.-Y., Pineda, Sandy S., Keramidas, Angelo, Mobli, Mehdi, Pham, Vi, De Silva, T. Michael, Lynch, Joseph W., Widdop, Robert E., Rash, Lachlan D. and King, Glenn F. (2017) Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a. Proceedings from the National Academy of Sciences of the United States of America, 114 14: 3750-3755. doi:10.1073/pnas.1614728114


Author Chassagnon, Irene R.
McCarthy, Claudia A.
Chin, Yanni K.-Y.
Pineda, Sandy S.
Keramidas, Angelo
Mobli, Mehdi
Pham, Vi
De Silva, T. Michael
Lynch, Joseph W.
Widdop, Robert E.
Rash, Lachlan D.
King, Glenn F.
Title Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a
Journal name Proceedings from the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2017-03-01
Year available 2017
Sub-type Article (original research)
DOI 10.1073/pnas.1614728114
Open Access Status Not yet assessed
Volume 114
Issue 14
Start page 3750
End page 3755
Total pages 6
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Abstract Stroke is the second-leading cause of death worldwide, yet there are no drugs available to protect the brain from stroke-induced neuronal injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor in mammalian brain and a key mediator of acidosis-induced neuronal damage following cerebral ischemia. Genetic ablation and selective pharmacologic inhibition of ASIC1a reduces neuronal death following ischemic stroke in rodents. Here, we demonstrate that Hi1a, a disulfide-rich spider venom peptide, is highly neuroprotective in a focal model of ischemic stroke. Nuclear magnetic resonance structural studies reveal that Hi1a comprises two homologous inhibitor cystine knot domains separated by a short, structurally well-defined linker. In contrast with known ASIC1a inhibitors, Hi1a incompletely inhibits ASIC1a activation in a pH-independent and slowly reversible manner. Whole-cell, macropatch, and single-channel electrophysiological recordings indicate that Hi1a binds to and stabilizes the closed state of the channel, thereby impeding the transition into a conducting state. Intracerebroventricular administration to rats of a single small dose of Hi1a (2 ng/kg) up to 8 h after stroke induction by occlusion of the middle cerebral artery markedly reduced infarct size, and this correlated with improved neurological and motor function, as well as with preservation of neuronal architecture. Thus, Hi1a is a powerful pharmacological tool for probing the role of ASIC1a in acid-mediated neuronal injury and various neurological disorders, and a promising lead for the development of therapeutics to protect the brain from ischemic injury.
Keyword Acid-sensing ion channel 1a
Ischemia
Neuroprotection
Stroke
Venom peptide
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1063798
Institutional Status UQ

 
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Created: Tue, 11 Apr 2017, 15:15:47 EST by Kirstie Asmussen on behalf of School of Music