Conformational Changes in the Lower Palm Domain of ASIC1a Contribute to Desensitization and RFamide ModulationReportar como inadecuado




Conformational Changes in the Lower Palm Domain of ASIC1a Contribute to Desensitization and RFamide Modulation - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

Acid-sensing ion channel 1a ASIC1a is a proton-gated cation channel that contributes to fear and pain as well as neuronal damage following persistent cerebral acidosis. Neuropeptides can affect acid-induced neuronal injury by altering ASIC1a inactivation and-or steady-state desensitization. Yet, exactly how ASIC1a inactivation and desensitization occur or are modulated by peptides is not completely understood. We found that regions of the extracellular palm domain and the β11-12 linker are important for inactivation and steady-state desensitization of ASIC1a. The single amino acid substitutions L280C and L415C dramatically enhanced the rate of inactivation and altered the pH-dependence of steady-state desensitization. Further, the use of methanethiosulfonate MTS reagents suggests that the lower palm region L280C undergoes a conformational change when ASIC1a transitions from closed to desensitized. We determined that L280C also displays an altered response to the RFamide peptide, FRRFamide. Further, the presence of FRRFamide limited MTS modification of L280C. Together, these results indicate a potential role of the lower palm domain in peptide modulation and suggest RFamide-related peptides promote conformational changes within this region. These data provide empirical support for the idea that L280, and likely this region of the central vestibule, is intimately involved in channel inactivation and desensitization.



Autor: Erin N. Frey, Ryan E. Pavlovicz, Clem John Wegman, Chenglong Li, Candice C. Askwith

Fuente: http://plos.srce.hr/



DESCARGAR PDF




Documentos relacionados