Implication of the C-terminal region of the alpha-subunit of voltage-gatedsodium channels in fast inactivation

The alpha -subunit of both the human heart (hH1) and human skeletal muscle (hSkM1) sodium channels were expressed in a mammalian expression system. Th e channels displayed slow (hH1) and fast (hSkM1) current decay kinetics sim ilar to those seen in native tissues. Hence, the aim of this study was to i dentify the region on the alpha -subunit involved in the differences of the se current-decay kinetics. A series of hH1/hSkM1 chimeric sodium channels w ere constructed with the focus on the C-terminal region. Sodium currents of chimeric channels were recorded using the patch-clamp technique in whole-c ell configuration, Chimeras where the C-terminal region had been exchanged between hH1 and hSkM1 revealed that this region contains the elements that cause differences in current decay kinetics between these sodium channel is oforms. Other biophysical characteristics (steady-state activation and inac tivation and recovery from inactivation) were similar to the phenotype of t he parent channel. This indicates that the C-terminus is exclusively implic ated in the differences of current decay kinetics. Several other chimeras w ere constructed to identify a specific region of the C-terminus causing thi s difference. Our results showed that the first 100-amino-acid stretch of t he C-terminal region contains constituents that could cause the differences in current decay between the heart and skeletal muscle sodium channels.