Na(v)1.7 sodium channel-induced Ca2+ influx decreases tau phosphorylation via glycogen synthase kinase-3 beta in adrenal chromaffin cells

作者：Kanai Tasuku; Nemoto Takayuki; Yanagita Toshihiko; Maruta Toyoaki; Satoh Shinya; Yoshikawa Norie; Wada Akihiko^*

来源：Neurochemistry International, 2009, 54(8): 497-505.

DOI：10.1016/j.neuint.2009.02.002

• Na(v)1.7 sodium channel
• Calcium
• Protein kinase C-alpha
• Akt
• Glycogen synthase kinase-3 beta
• Tau

In cultured bovine adrenal chromaffin cells expressing Na(v)1.7 sodium channel isoform, veratridine increased Ser(473)-phosphorylation of Akt and Ser(396)-phosphorylation of glycogen synthase kinase-3 beta by similar to 217 and similar to 195%, while decreasing Ser(396)-phosphorylation of tau by similar to 36% in a concentration (EC50 = 2.1 mu M)- and time (t(1/2) = 2.7 min)-dependent manner. These effects of veratridine were abolished by tetrodotoxin or extracellular Ca2+ removal. Veratridine (10 mu M for 5 min) increased translocation of Ca2+-dependent conventional protein kinase C-alpha from cytoplasm to membranes by 47%; it was abolished by tetrodotoxin, extracellular Ca2+ removal, or Go6976 (an inhibitor of protein kinase C-alpha), and partially attenuated by LY294002 (an inhibitor of phosphatidylinositol 3-kinase). LY294002 (but not G06976) abrogated veratridine-induced Akt phosphorylation. In contrast, either LY294002 or Go6976 alone attenuated veratridine-induced glycogen synthase kinase-3 beta phosphorylation by 65 or 42%; however, LY294002 plus G06976 completely blocked it. Veratridine (10 mu M for 5 min)-induced decrease of tau phosphorylation was partially attenuated by LY294002 or Go6976, but completely blocked by LY294002 plus Go6976; 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 Ca2+ influx via voltage-dependent calcium channel activated (1) Ca2+/ protein kinase C-alpha pathway, as well as (2) Ca2+/phosphatidylinositol 3-kinase/Akt and (3) Ca2+/ phosphatidylinositol 3-kinase/protein kinase C-alpha pathways; these parallel pathways converged on inhibitory phosphorylation of glycogen synthase kinase-3 beta, decreasing tau phosphorylation.

• 出版日期2009-7