Role of the amino and carboxy termini in isoform-specific sodium channel variation.
Na(v)1.2 and Na(v)1.6 are two voltage-gated sodium channel isoforms found in adult CNS neurons. These isoforms differ in their electrophysiological properties, even though the major regions that are known to be involved in channel activation and inactivation are conserved between them. To determine if the terminal domains of these channels contributed to their activation and fast inactivation differences, we constructed chimeras between the two isoforms and characterized their electrophysiological properties. Exchanging the N-terminal 205 amino acids of Na(v)1.6 and the corresponding 202 amino acids of Na(v)1.2 completely swapped the V_(1)/(2) of steady-state activation between the Na(v)1.2 and Na(v)1.6 channels in an isoform-specific manner. Exchanging the C-terminal 436 amino acids of Na(v)1.6 and the corresponding region of Na(v)1.2 altered the voltage dependence and kinetics of steady-state inactivation, but the changes did not reflect a direct transfer of inactivation properties between the two isoforms. Finally, the N- and C-terminal domains from Na(v)1.6 demonstrated functional cooperation. These results suggest that the terminal sequences of the sodium channel are important for isoform-specific differences between the channels.
Lee
Annie
A
Department of Microbiology and Molecular Genetics, University of California, Irvine, CA 92697-4025, USA.
Goldin
Alan L
AL
D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D008564:Membrane Potentials / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C568251:SCN2A protein, human; C100681:SCN8A protein, human; D015222:Sodium Channels; D012964:Sodium