Effects of lithium in vitro and ex vivo on components of the adenylate cyclase system in membranes from the cerebral cortex of the rat

The effects of lithium on the activity of adenylate cyclase stimulated by hormones, which act via the stimultory guanine nucleotide binding subunit (N_s), by forskolin, which acts at the catalytic subunit, and by guanyl-5'-yl imidodiphosphate (GppNHp), which locks the enzyme into a permanently active state, have been compared in a preparation of membranes from the cerebral cortex of the rat. Lithium ions (Li⁺) in vitro at 2-4 mM inhibited cyclase stimulated by isoproterenol and forskolin, but had no effect on the inhibition induced by met-enkephalin of the enzyme stimulated by forskolin, mediated by the inhibitory guanine nucleotide binding subunit (N_i). Inhibition of the activity stimulated by forskolin and GppNHp was competitive with magnesium (Mg⁺⁺). In a preparation of slices of cerebral cortex Li ⁺ at 1-2 mM inhibited accumulation of cyclic AMP stimulated by forskolin in a non-competitive manner. In a preparation of membranes from the caudate nucleus, Li⁺ at 2-4 mM inhibited dopamine-stimulated adenylate cyclase, but this effect was not observed in the presence of additional sodium (Na⁺). Membranes prepared from animals fed with Li⁺ to give a mean serum level of 0.52 mM and a mean brain level of 1.32 mM, showed a reduced response to manganese (Mn^{+ +}), forskolin, isoproterenol and GppNHp in the cerebral cortex, but no change in the degree of activation of the enzyme by either dopamine or forskolin, or the degree of inhibition by met-enkephalin, in the caudate nucleus. It is concluded that Li⁺ inhibits adenylate cyclase at a site on the enzyme beyond the receptor, possibly the catalytic unit or a binding site for metal ions associated with the N_s unit.