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Molecular cloning, distribution and functional analysis of the NAV1.6. Voltage-gated sodium channel from human brain

2002; Elsevier BV; Volume: 103; Issue: 1-2 Linguagem: Inglês

10.1016/s0169-328x(02)00188-2

1872-6941

Stephen A. Burbidge, Timothy Dale, Andrew J. Powell, William R. J. Whitaker, Xinmin Xie, Michael A. Romanos, Jeffrey J. Clare,

Cardiac electrophysiology and arrhythmias

We have cloned and expressed the full-length human NaV1.6 sodium channel cDNA. Northern analysis showed that the hNaV1.6 gene, like its rodent orthologues, is abundantly expressed in adult brain but not other tissues including heart and skeletal muscle. Within the adult brain, hNaV1.6 mRNA is widely expressed with particularly high levels in the cerebellum, occipital pole and frontal lobe. When stably expressed in human embryonic kidney cells (HEK293), the hNaV1.6 channel was found to be very similar in its biophysical properties to human NaV1.2 and NaV1.3 channels [Eur. J. Neurosci. 12 (2000) 4281–4289; Pflügers Arch. 441 (2001) 425–433]. Only relatively subtle differences were observed, for example, in the voltage dependence of gating. Like hNaV1.3 channels, hNaV1.6 produced sodium currents with a prominent persistent component when expressed in HEK293 cells. These persistent currents were similar to those reported for the rat NaV1.2 channel [Neuron 19 (1997) 443–452], although they were not dependent on over-expression of G protein βγ subunits. These data are consistent with the proposal that NaV1.6 channels may generate the persistent currents observed in cerebellar Purkinje neurons [J. Neurosci. 17 (1997) 4157–4536]. However, in our hNaV1.6 cell line we have been unable to detect the resurgent currents that have also been described in Purkinje cells. Although NaV1.6 channels have been implicated in producing these resurgent currents [Neuron 19 (1997) 881–891], our data suggest that this may require modification of the NaV1.6 α subunit by additional factors found in Purkinje neurons but not in HEK293 cells.