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 of 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.
D000255:Adenosine Triphosphate / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000273:Adipose Tissue / Q000166:cytology / Q000201:enzymology*; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology; D008094:Lithium / Q000494:pharmacology*; D008274:Magnesium / Q000494:pharmacology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000067956:Adenylyl Cyclase Inhibitors; D000255:Adenosine Triphosphate; D008094:Lithium; D008274:Magnesium; D005459:Fluorides; D002118:Calcium; D009638:Norepinephrine