MODULATION OF CARDIAC SODIUM-CHANNEL ISOFORM BY CYCLIC-AMP-DEPENDENT PROTEIN-KINASE DOES NOT DEPEND ON PHOSPHORYLATION OF SERINE-1504 IN THE CYTOSOLIC LOOP INTERCONNECTING TRANSMEMBRANE DOMAIN-III AND DOMAIN-IV

Both the neuronal IIA as well as the cardiac SkM2 isoform of the pore forming alpha-subunit of voltage dependent sodium channels are modulated by Protein Kinase A. While alpha(IIA) becomes attenuated upon PKA stimulation, alpha(SkM2) becomes upregulated. PKC dependent phosphorylation of a serine, located in the highly conserved cytoplasmatic region between the third and the fourth transmembraneous domain has been found to be a prerequisite for PKA modulation of the alpha(IIA) isoform. We used site-directed mutagenesis, expression in Xenopus laevis oocytes and the two-electrode voltage clamp technique to test, whether phosphorylation of the corresponding serine in alpha(SkM2) is required for the PKA modulation of also the cardiac isoform. The results clearly indicate that serine 1504 does not play a significant role in the PKA modulation of the cardiac sodium channel isoform, further underlining the differential modulation of the two isoforms by identical signal transduction cascades.