On the Mechanism of Inhibition of Rat Fat Cell Adenylate Cyclase by Lithium

: This study aimed to elucidate the mechanism by which Li+ inhibits adenylate cyclase (AC) in vitro. It was found that Li+ inhibited the norepinephrine- (NE) and the fluoride- (F) stimulated AC activities of rat fat cell ghosts at Li+ concentrations above 10 mM. The basal enzyme activity was unaffected even at 80 mM of Li+. Li+ inhibited the NE-induced AC activity in a mainly non-competitive way, but the inhibitory effect decreased with increasing concentrations of NE. The inhibition by Li+ of both NE- and F--stimulated AC activities was antagonized by Mg2+. The Mg2+ antagonism of the Li+-induced inhibition of the NE-stimulated AC activity was independent of the NE concentration. Furthermore, Ca2+, inhibiting AC activity by a Mg2+ antagonism, abolished the inhibitory effect of Li+. It is suggested that Li+ affects both the Ka of NE and the Vmax of AC through 1) an inhibitory action of LiATP3- at the catalytic site of AC or 2) an inhibitory action of Li+ at an allosteric Mg2+ site of AC.