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 domains III and IV

Abstract

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 alphaIIA becomes attenuated upon PKA stimulation, alphaSkM2 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 alphaIIA 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 alphaSkM2 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.