Lithium preferentially inhibits adenylyl cyclase V and VII isoforms

Lithium ions' inhibition of adenylyl cyclase (AC) has not been previously studied for the newly discovered AC isoforms. COS7 cells were transfected with each of the nine membrane-bound AC isoforms cDNAs with or without D1- or D2-dopamine receptor cDNA. AC activity was measured as [3H]cAMP accumulation in cells pre-incubated with [3H]adenine followed by incubation with phosphodiesterase inhibitors together with either the D1 agonist SKF-82958 alone, or forskolin, in the presence or absence of the D2 agonist quinpirole. At 1 mm or 2 mm lithium inhibited only AC-V activity when the enzyme was stimulated by forskolin, a direct activator of AC. Lithium inhibited AC-V (by 50%), AC-VII (by 40%) and AC-II (by 25%) when stimulated via the D1 receptors, but did not affect the Ca2+-activated isoforms when stimulated by the Ca2+ ionophore A23187. Quinpirole inhibits AC via the Gi protein. Lithium did not affect quinpirole-inhibited FSK-activated AC-V activity nor did it affect superactivated AC-V or AC-I following the removal of quinpirole. The data suggest interference of lithium with transduction pathways mediated via AC-V or AC-VII; only the active conformation of these AC isoforms is inhibited by lithium; the inhibitory effect of lithium is abolished when the enzyme is superactivated. The marked inhibition of AC-V and AC-VII by lithium suggests that these two isoforms may be involved in mediating the mood-stabilizing effect of lithium.