Poster abstracts

Poster number 81 submitted by Thomas Sherwood

Cross-talk between G protein-coupled receptors and Acid-Sensing Ion Channel 1a determine neuronal outcome to pathological acidosis

Thomas Sherwood (Department of Neuroscience, College of Medicine), Candice Askwth (Department of Neuroscience, College of Medicine)

Abstract:
During cerebral ischemia there is a prolonged decrease in extracellular pH and increased release of Dynorphin opioid peptides. Extracellular acidosis induces neuronal death by activating the Acid-Sensing Ion Channels (ASICs). Preventing ASIC1a activation through genetic manipulation or pharmacological treatment substantially reduces ischemic death in middle-cerebral artery occlusion models of stroke. Thus, ASIC1a is a compelling target for therapeutic treatment to limit brain damage following stroke. Dynorphin peptides have a less defined role in ischemia as they can act on a multitude of receptors to induce both neurotoxic and neuroprotective effects. However, their role in acid-induced death has not been reported. We have discovered that Dynorphin peptides prevent ASIC-mediated death following rapid acidosis in cultured cortical neurons by activation of a naloxone/B9430-sensitive G protein coupled receptor (GPCR) pathway. Surprisingly, we find using electrophysiological recording that Dynorphins directly potentiate ASIC1a current by preventing an intrinsic channel property known as steady-state desensitization. Further, we find that Dynorphin treatment strongly enhances acid-induced neuronal death following incremental pH decline that otherwise desensitizes ASIC1a. Taken together, this data suggests that Dynorphin peptides regulate neuron survival during pathological acidosis by coordinating G protein-coupled receptor and pH-receptor signaling.

Keywords: stroke, opioid, peptide