Lithium preferentially inhibits adenylyl cyclase V and VII isoforms
Lithium preferentially inhibits adenylyl cyclase V and VII isoforms
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DOI：
10.1017/s1461145707008395
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发表时间：
2008-06-01
影响因子：
4.8
通讯作者：
Agam, Galila
中科院分区：
文献类型：
--
作者：
Mann, Liad;Heldman, Eliahu;Agam, Galila
对于新发现的腺酰环化酶(AC)异构体，锂离子对AC的抑制作用尚未见报道。将9种膜结合型AC亚型的cDNA分别与D-1或D-2-多巴胺受体基因共转染COS7细胞。AC活性测定为预先与[H-3]腺嘌呤孵育的细胞中[H-3]cAMP积聚，然后与磷酸二酯酶抑制剂和D激动剂SKF-82958一起孵育，或在D-2激动剂奎比罗存在或不存在的情况下与Forsklin孵育。在1 mM或2 mM锂离子浓度下，当AC的直接激活剂Forskolin刺激该酶时，仅抑制AC-V的活性。当通过D-1受体刺激时，锂抑制AC-V(50%)、AC-VII(40%)和AC-II(25%)，但当被钙离子载体A23187刺激时，不影响钙激活的异构体。昆匹罗通过胃肠道蛋白抑制AC。锂不影响奎比罗抑制的FSK激活的AC-V活性，也不影响奎比罗去除后激活的AC-V或AC-I。这些数据表明，锂干扰了AC-V或AC-VII介导的转导通路；只有这些AC异构体的活性构象被锂抑制；抑制剂)，当酶被过度激活时，锂的作用被取消。锂对AC-V和AC-VII有明显的抑制作用，提示这两种异构体可能参与了锂的情绪稳定作用。
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 D-1- or D-2-dopamine receptor cDNA. AC activity was measured as [H-3]cAMP accumulation in cells pre-incubated with [H-3]adenine followed by incubation with phosphodiesterase inhibitors together with either the D, agonist SKF-82958 alone, or forskolin, in the presence or absence of the D-2 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 D-1 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 inhibitor), 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.