Изучение роли С-концевого внутриклеточного домена на функционирование ионного канала ASIC3

Increasing of protons concentration in the synaptic cleft during neurotransmitters release is considered as a possible way for the postsynaptic membrane sensitization. The main sensors of acidification are acid-sensing ion channels (ASICs). The ASIC3 localized on the sensing neurons membrane well contributed to the perception of pain and is considered as one of promising target for a novel therapeutic agents development. Despite the high degree of homology between mammalian ASIC3 channels, there are a number of differences for their orthologs present. One potent difference among human and rat ASIC3 is a respond to fast acidic stimulus at physiological pH 7.4. Human ASIC3 produces particularly solitary sustained current through membrane, while rat has a transient current before sustained component. In this paper, we showed the importance of C-terminal intracellular domain (CTD) for a regulatory function of the transient current development in human and rat ASIC3. Shortening of CTD by 20 amino acid residues leads to a dramatically increase of transient current and attenuation of the sustained current, while CTD modification in hASIC3 leads to the appearance of a well-defined transient current like rASIC3, which was demonstrated in whole-cell experiments for heterologously expressed channels. Also, the deletion of 20 amino acid residues in CTD increased the current amplitude by an order of magnitude in both rASIC3 and hASIC3. The obtained results demonstrate the special role of CTD in the intracellular regulation of ASIC3 channels.