Transient increases in intracellular calcium result in prolonged site-selective increases in tau phosphorylation through a glycogen synthase kinase 3beta-dependent pathway

Calcium is a universal intracellular signaling molecule, Through variations in both the amplitude and frequency of intracellular calcium increases, th e same calcium ion can elicit different responses. In this report, we inves tigated the effect of a calcium transient, lasting 2-5 min, on alterations in the phosphorylation state of the cytoskeletal protein, tau, Transient in creases in calcium result in a prolonged (1-4 h) similar to 60% increase in tau phosphorylation at the Tau-1 epitope, These increases in tau phosphory lation appear to be more dependent upon the duration of the increase in int racellular calcium and less on the amplitude, The calcium-induced increases in tau phosphorylation are not dependent upon protein synthesis, nor are p rotein kinase C or calcium/calmodulin-dependent protein kinase II involved in the response. However, the calcium-induced increase in tau phosphorylati on was inhibited by lithium, a noncompetitive inhibitor of glycogen synthas e kinase-3 beta (GSK-3 beta), and by the tyrosine kinase inhibitor, geniste in, Furthermore, transient increases in calcium resulted in a prolonged inc rease in GSK-3 beta tyrosine phosphorylation concomitant with the increase in tau phosphorylation, Therefore, this study is the first to indicate that transient increases in intracellular calcium result in increased tyrosine phosphorylation and activation of GSK-3 beta which subsequently results in a sustained increase in the phosphorylation state of tau.