Role of calmodulin in states of altered catecholamine sensitivity.

Calmodulin, an endogenous calcium-binding protein, can modulate the intracellular concentration of adenosine 3',5'-cyclic monophosphate (cyclic AMP] by stimulating membrane-bound adenylate cyclase activity and soluble phosphodiesterase (PDE) activity.' There is increasing evidence that calmodulin can modulate the effects of calcium at both preand postsynaptic sites in some areas of brain. Calmodulin is enriched in rat brain synaptic membranes2 and has been located in postsynaptic densities in mouse basal ganglia3 and canine cerebral ~ o r t e x . ~ Previous studies have suggested that calmodulin is involved with dopamine IDA)-sensitive adenylate cyclase activity in rat striaturn. Gnegy et aL5 found that depletion of calmodulin t'rom striatal membranes results in a decreased ability of DA to stimulate adenylate cyclase activity. Furthermore, the calmodulin content in the striaturn was increased under conditions of dopamine supersensitivity.6 Rats treated chronically with cataleptogenic antipsychotic drugs and then withdrawn from the drugs hail increased calmodulin content in their striatal membranes. These animals exhibited behavioral supersensitivity to apomorphine and their striatal adenylate cyclase had an increased affinity for dopamine as demonstrated by a 3to 4-foid increase in dopamine sensitivity. The increase in calmodulin could positively affect DA-sensitive adenylate cyclase activity and thus contribute to dopaminergic: supersensitivity. The increased calmodulin in the striatal membranes of the supersensitive rats seems to be more tightly bound to its membrane binding protein^.^ In the brain, calmodulin can be hound to membrane proteins in a calcium-dependent and calcium-independent manner.' Calmodulin has been shown to hind to Caz+dependent PDE' and Caz+-sensitive adenylate cyclase'o as well as other proteins. Vandermeers et (11." have demonstrated a correlation between increased ['ZSI]calmodulin binding and activation of adenylate cyclase activity in guinea pig membranes. In this work we investigate more directly whether calmodulin can affect DA-sensitive activity in rat striatal membranes. We found that calmodulin could affect both the maximal velocity of the reaction and the sensitivity to DA. We studied the binding of calmodulin to striatal membranes in order to further investigate the relationship between calmodulin interaction with adenylate cyclase activity. We showed specific binding of ['251]calmodulin to striatal membranes that was competitively inhibited by trifluoperazine, an antipsychotic drug that binds to calmodulin and inhibits its action." We have also shown that the ability of the calmodulin content to increase could be specific for dopaminergic supersensitivity in the striatum.