title: Lithium preferentially inhibits adenylyl cyclase V and VII isoforms.
abstract: 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.
authors.affiliation: Stanley Research Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Liad
authors.initials: L
authors.lastname: Mann
authors.forename: Eliahu
authors.initials: E
authors.lastname: Heldman
authors.forename: Galit
authors.initials: G
authors.lastname: Shaltiel
authors.forename: R H
authors.initials: RH
authors.lastname: Belmaker
authors.forename: Galila
authors.initials: G
authors.lastname: Agam
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000235:genetics; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D019556:COS Cells; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004791:Enzyme Inhibitors; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000235:genetics; D018021:Lithium Chloride / Q000494:pharmacology*; D010957:Plasmids / Q000235:genetics; D017447:Receptors, Dopamine D1 / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D013469:Sulpiride / Q000494:pharmacology; D014162:Transfection
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D017447:Receptors, Dopamine D1; D005576:Colforsin; D000001:Calcimycin; D013469:Sulpiride; C071262:SK&F 82958; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C473265:adenylyl cyclase 7; C419510:adenylyl cyclase type V; D018021:Lithium Chloride