ASICs and neuropeptides

The acid sensing ion channels (ASICs) are proton-gated cation channels expressed throughout the nervous system. ASICs are activated during acidic pH fluctuations, and recent work suggests that they are involved in excitatory synaptic transmission. ASICs can also induce neuronal degeneration and death during pathological extracellular acidosis caused by ischemia, autoimmune inflammation, and traumatic injury. Many endogenous neuromodulators target ASICs to affect their biophysical characteristics and contributions to neuronal activity. One of the most unconventional types of modulation occurs with the interaction of ASICs and neuropeptides. Collectively, FMRFamide-related peptides and dynorphins potentiate ASIC activity by decreasing the proton-sensitivity of steady state desensitization independent of G protein-coupled receptor activation. By decreasing the proton-sensitivity of steady state desensitization, the FMRFamide-related peptides and dynorphins permit ASICs to remain active at more acidic basal pH. Unlike the dynorphins, some FMRFamide-related peptides also potentiate ASIC activity by slowing inactivation and increasing the sustained current. Through mechanistic studies, the modulation of ASICs by FMRFamide-related peptides and dynorphins appears to be through distinct interactions with the extracellular domain of ASICs. Dynorphins are expressed throughout the nervous system and can increase neuronal death during prolonged extracellular acidosis, suggesting that the interaction between dynorphins and ASICs may have important consequences for the prevention of neurological injury. The overlap in expression of FMRFamide-related peptides with ASICs in the dorsal horn of the spinal cord suggests that their interaction may have important consequences for the treatment of pain during injury and inflammation. This article is part of the Special Issue entitled 'Acid-Sensing Ion Channels in the Nervous System'.