Endogenous Rfamide-related Peptides Alter Steady-state Desensitization of Asic1a

The acid sensing ion channels (ASICs) are proton-gated, voltage-insensitive cation channels expressed throughout the nervous system. ASIC1a plays a role in learning, pain, and fear related behaviors. In addition, activation of ASIC1a during prolonged acidosis following cerebral ischemia induces neuronal death. ASICs undergo steady-state desensitization, a characteristic that limits ASIC1a activity and may play a prominent role in the prevention of ASIC1a-evoked neuronal death. In this project, we found exogenous and endogenous RFamide-related peptides decreased the pH sensitivity of ASIC1a steadystate desensitization. During conditions that normally induced steady-state desensitization, these peptides profoundly enhanced ASIC1a activity. We also determined that human ASIC1a required more acidic pHs to undergo steady-state desensitization compared to mouse ASIC1a. Surprisingly, steady-state desensitization of human ASIC1a was also affected by a greater number of peptides compared to mouse ASIC1a. Mutation of five amino acids in a region of the extracellular domain changed the characteristics of human ASIC1a to those of mouse ASIC1a, suggesting that this region plays a pivotal role in neuropeptide and pH sensitivity of steady-state desensitization. Overall, these experiments lend vital insight into steady-state desensitization of ASIC1a and expand our understanding of the structural determinants of RFamide-related peptide modulation. Further, our finding that endogenous peptides shift steady-state desensitization suggests that RFamides could http://www.jbc.org/cgi/doi/10.1074/jbc.M705118200 The latest version is at JBC Papers in Press. Published on November 5, 2007 as Manuscript M705118200