Gsα-selective G protein antagonists
Gsα-selective G protein antagonists
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DOI：
10.1073/pnas.95.1.346
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发表时间：
1998-01-06
影响因子：
11.1
通讯作者：
Freissmuth, M
中科院分区：
文献类型：
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作者：
Hohenegger, M;Waldhoer, M;Freissmuth, M
苏拉明作为G蛋白抑制剂起作用，因为它抑制G（α）亚基活化中的限速步骤，即，在这里，我们已经搜索了对G（s α）具有选择性的类似物。已鉴定出两种化合物：NF 449（4，4 '，4“，4”'-[羰基-双[亚氨基-5，1，3-苯三基双-（羰基亚氨基）]]四-（苯-1，3-二磺酸盐）和NF 503（4，4 '-[羰基双[亚氨基-3，1-亚苯基-（2，5-苯并咪唑亚基）羰基亚氨基]]双-苯磺酸盐）。这些化合物（i）抑制鸟苷5 ′-[γ-硫代]三磷酸的结合速率（[S-35] GTP [γ S]）与G结合（s α-s）但不是G（i α-1），（ii）抑制S49 cyc（-）膜中腺苷酸环化酶活性的刺激（缺乏内源性G（s α））通过外源性添加G（s α-s），和（iii）阻断β-肾上腺素能受体与G（s）的偶联，半最大效应在低微摩尔范围内。与非选择性的苏拉明相反，NF 503和NF 449破坏A（1）-腺苷受体与其同源G蛋白（G（i）/G（o））的相互作用，其浓度比β-肾上腺素能受体/G（s）串联体解偶联所需的浓度高>30倍;类似地，血管紧张素II 1型受体（原型G（q）-偶联受体）几乎不受化合物的影响。因此，NF 503和NF 449满足G（s α）选择性拮抗剂的基本标准。观察结果表明亚型选择性G蛋白抑制的可行性。
Suramin acts as a G protein inhibitor because it inhibits the rate-limiting step in activation of the G(alpha) subunit, i.e., the exchange of GDP for GTP, Here, we have searched for analogues that are selective for G(s alpha). Two compounds have been identified: NF449 (4,4',4 ",4'''-[carbonyl-bis [imino-5,1,3-benzenetriyl bis-(carbonylimino)]]tetrakis-(benzene-1,3-disulfonate) and NF503 (4,4'-[carbonylbis[imino-3,1-phenylene-(2,5-benzimidazolylene) carbonylimino]] bis-benzenesulfonate). These compounds (i) suppress the association rate of guanosine 5'-[gamma-thio] triphosphate ([S-35] GTP [gamma S]) binding to G(s alpha-s) but not to G(i alpha-1), (ii) inhibit stimulation of adenylyl cyclase activity in S49 cyc(-) membranes (deficient in endogenous G(s alpha)) by exogenously added G(s alpha-s), and (iii) block the coupling of beta-adrenergic receptors to G(s) with half-maximum effects in the low micromolar range. In contrast to suramin, which is not selective, NF503 and NF449 disrupt the interaction of the A(1)-adenosine receptor with its cognate G proteins (G(i)/G(o)) at concentrations that are >30-fold higher than those required for uncoupling of beta-adrenergic receptor/G(s) tandems; similarly, the angiotensin II type-1 receptor (a prototypical G(q)-coupled receptor) is barely affected by the compounds. Thus, NF503 and NF449 fulfill essential criteria for G(s alpha)-selective antagonists. The observations demonstrate the feasibility of subtype-selective G protein inhibition.