The Effect of Lithium on Adenylyl Cyclase: Thirty-Five Years of Research (1975∼2010)
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One of the first discovered effects of lithium was inhibition of adenylyl cyclase (AC). AC is linked to many brain receptors and transmits their message into the cell by catalyzing the formation of cyclic AMP from adenosine triphosphate. Since the original report found lithium inhibition at 2 mM we attempted to see whether this effect actually occurred in patients on lithium whose average blood levels are less than 1 mM. We were able to show this effect using subcutaneous adrenalin and measuring cyclic AMP in plasma over the course of 70 minutes. We then studied the specificity of the effect using the glucagon induced rise in plasma cyclic AMP and found no effect of lithium. In rat brain slices we could confirm the finding that lithium inhibition occurs only at 2 mM but we could show that chronic lithium treated rats had inhibition of cyclic AMP accumulation ex vivo. Since the AC system is complex we attempted to find the site of lithium action. Lithium inhibited G-protein function induced by isoproterenol or carbachol as measured by increases in rat brain homogenate radioactive GTP binding. However, lithium inhibited forskolin induced rises in cAMP accumulation and forskolin is thought to stimulate the AC system directly at the enzyme even in the absence of G-protein. More recently, 10 different isozymes of AC have been described, each the product of a different gene and with differential location throughout the brain or peripheral tissues. We were able to show that lithium preferentially inhibits AC5 and to a lesser extent AC2 and AC7. Since AC5 is located mostly in dopamine rich areas in the basal ganglia, this suggested that lithium’s specific behavioral effects might be related to AC5. The effect of lithium on AC5 is magnesium dependent, similar to the effect of lithium in many other biochemical systems. AC remains a candidate for the therapeutic mechanism of lithium and AC5 inhibitors under development may be brought to clinical trial in bipolar illness.
Abstract
One of the first discovered effects of lithium was inhibition of adenylyl cyclase (AC). AC is linked to many brain receptors and transmits their message into the cell by catalyzing the formation of cyclic AMP from adenosine triphosphate. Since the original report found lithium inhibition at 2 mM we attempted to see whether this effect actually occurred in patients on lithium whose average blood levels are less than 1 mM. We were able to show this effect using subcutaneous adrenalin and measuring cyclic AMP in plasma over the course of 70 minutes. We then studied the specificity of the effect using the glucagon induced rise in plasma cyclic AMP and found no effect of lithium. In rat brain slices we could confirm the finding that lithium inhibition occurs only at 2 mM but we could show that chronic lithium treated rats had inhibition of cyclic AMP accumulation ex vivo. Since the AC system is complex we attempted to find the site of lithium action. Lithium inhibited G-protein function induced by isoproterenol or carbachol as measured by increases in rat brain homogenate radioactive GTP binding. However, lithium inhibited forskolin induced rises in cAMP accumulation and forskolin is thought to stimulate the AC system directly at the enzyme even in the absence of G-protein. More recently, 10 different isozymes of AC have been described, each the product of a different gene and with differential location throughout the brain or peripheral tissues. We were able to show that lithium preferentially inhibits AC5 and to a lesser extent AC2 and AC7. Since AC5 is located mostly in dopamine rich areas in the basal ganglia, this suggested that lithium’s specific behavioral effects might be related to AC5. The effect of lithium on AC5 is magnesium dependent, similar to the effect of lithium in many other biochemical systems. AC remains a candidate for the therapeutic mechanism of lithium and AC5 inhibitors under development may be brought to clinical trial in bipolar illness.
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