科研之友
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摘要
Voltage dependent sodium channels are membrane proteins essential for cell excitability. They are composed by a pore-forming alpha-subunit, encoded in mammals by up to 9 different genes, and 4 different ancillary beta-subunits. The expression pattern of the alpha subunit isoforms confers the distinctive functional and pharmacological properties to different excitable tissues. beta subunits are important modulators of channel function and expression. Mutation C121W of the beta 1-subunit causes an autosomal dominant epileptic syndrome without cardiac symptoms. The C121W mutation may act by a dominant-competition, modifying the expression of alpha-subunit proteins. To test this hypothesis, we transfected GH3 cells, from neuro-ectoderm origin, with wild-type or mutant beta 1 subunits and compared them to native cells. To examine the tissue specificity of the C121W-beta 1 mutation, we compared the effects of the mutation on neural cells with those of H9C2 cells of cardiac origin. We found that in GH3 cells the over-expression of the beta 1 subunit augments the alpha subunit mRNA and protein levels, while in the H9C2 cells the enhanced level of beta 1 subunit not only increases but also qualitatively modifies the sodium channel alpha isoform expression pattern. Interestingly, the introduction of the epileptogenic C121W-beta 1 subunit does not alter the sodium channel isoform composition of GH3 cells, while produces additional changes in the alpha-subunit expression pattern of H9C2 cells. Electrophysiological measurements confirm these molecular results. The expression differences observed could be correlated to the tissue-specific regulatory action of the beta 1 subunit and to the nervous system specificity of the C121W mutation. Our findings could be helpful for the comprehension of the molecular mechanism of generalised epileptic with febrile seizures plus in patients with identified beta 1 subunit mutations.
- 出版日期2013-8
