Nav1.7 sodium channel-induced Ca2+ influx decreases tau phosphorylation via glycogen synthase kinase-3beta in adrenal chromaffin cells.

In cultured bovine adrenal chromaffin cells expressing Na(v)1.7 sodium channel isoform, veratridine increased Ser(473)-phosphorylation of Akt and Ser(9)-phosphorylation of glycogen synthase kinase-3beta by approximately 217 and approximately 195%, while decreasing Ser(396)-phosphorylation of tau by approximately 36% in a concentration (EC(50)=2.1 microM)- and time (t(1/2)=2.7 min)-dependent manner. These effects of veratridine were abolished by tetrodotoxin or extracellular Ca(2+) removal. Veratridine (10 microM for 5 min) increased translocation of Ca(2+)-dependent conventional protein kinase C-alpha from cytoplasm to membranes by 47%; it was abolished by tetrodotoxin, extracellular Ca(2+) removal, or Gö6976 (an inhibitor of protein kinase C-alpha), and partially attenuated by LY294002 (an inhibitor of phosphatidylinositol 3-kinase). LY294002 (but not Gö6976) abrogated veratridine-induced Akt phosphorylation. In contrast, either LY294002 or Gö6976 alone attenuated veratridine-induced glycogen synthase kinase-3beta phosphorylation by 65 or 42%; however, LY294002 plus Gö6976 completely blocked it. Veratridine (10 microM for 5 min)-induced decrease of tau phosphorylation was partially attenuated by LY294002 or Gö6976, but completely blocked by LY294002 plus Gö6976; okadaic acid or cyclosporin A (inhibitors of protein phosphatases 1, 2A, and 2B) failed to alter tau phosphorylation. These results suggest that Na(+) influx via Na(v)1.7 sodium channel and the subsequent Ca(2+) influx via voltage-dependent calcium channel activated (1) Ca(2+)/protein kinase C-alpha pathway, as well as (2) Ca(2+)/phosphatidylinositol 3-kinase/Akt and (3) Ca(2+)/phosphatidylinositol 3-kinase/protein kinase C-alpha pathways; these parallel pathways converged on inhibitory phosphorylation of glycogen synthase kinase-3beta, decreasing tau phosphorylation.

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