Millar J B, Rozengurt E
Imperial Cancer Research Fund, London, United Kingdom.
J Biol Chem. 1990 Nov 15;265(32):19973-9.
Prolonged exposure of Swiss 3T3 cells to vasopressin causes heterologous mitogenic desensitization to bombesin and structurally related peptides including gastrin-releasing peptide (GRP) without down-regulation of the bombesin receptor. The number and affinity of bombesin/GRP receptor sites and modulation of 125I-GRP binding by guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) are unaffected in membrane preparations from vasopressin-treated cultures. Stimulation of inositol phosphate accumulation, mobilization of intracellular calcium, production of diacylglycerol, and transmodulation of the epidermal growth factor receptor by bombesin are similarly unaffected. Thus, the heterologous mitogenic desensitization is not due to uncoupling of bombesin receptor from transducing G protein(s) or to an inability to activate phospholipase C. Bombesin, unlike vasopressin, causes a rapid dose-dependent release of [3H]arachidonic acid and prostaglandin E2 from Swiss 3T3 cells (EC50 approximately 4 nM), which is inhibited by the specific bombesin receptor antagonist [Leu13-psi(CH2NH)-Leu14]bombesin. Crucially, release of [3H]arachidonic acid and prostaglandin E2 by bombesin is completely suppressed by prolonged pretreatment with vasopressin (EC50 = 0.6 nM). The mitogenic action of bombesin is restored by adding arachidonic acid to vasopressin-treated cells. We conclude first that arachidonic acid release is an early signal in the mitogenic response to bombesin and second that pretreatment with vasopressin induces heterologous mitogenic desensitization to bombesin by a novel mechanism: inhibition of arachidonic acid release.
将瑞士3T3细胞长期暴露于血管加压素会导致对蛙皮素以及包括胃泌素释放肽（GRP）在内的结构相关肽产生异源有丝分裂脱敏，而蛙皮素受体不会下调。在来自血管加压素处理过的培养物的膜制剂中，蛙皮素/GRP受体位点的数量和亲和力以及鸟苷5'-O-(3-硫代三磷酸)（GTPγS）对125I-GRP结合的调节均未受影响。蛙皮素对肌醇磷酸积累的刺激、细胞内钙的动员、二酰基甘油的产生以及表皮生长因子受体的转调节同样未受影响。因此，异源有丝分裂脱敏并非由于蛙皮素受体与转导G蛋白解偶联或无法激活磷脂酶C所致。与血管加压素不同，蛙皮素会导致瑞士3T3细胞快速剂量依赖性释放[3H]花生四烯酸和前列腺素E2（EC50约为4 nM），这一过程被特异性蛙皮素受体拮抗剂[Leu13-psi(CH2NH)-Leu14]蛙皮素所抑制。至关重要的是，通过血管加压素长时间预处理（EC50 = 0.6 nM）可完全抑制蛙皮素引起的[3H]花生四烯酸和前列腺素E2释放。向血管加压素处理过的细胞中添加花生四烯酸可恢复蛙皮素的有丝分裂作用。我们首先得出结论，花生四烯酸释放是对蛙皮素的有丝分裂反应中的早期信号，其次得出结论，血管加压素预处理通过一种新机制诱导对蛙皮素的异源有丝分裂脱敏：抑制花生四烯酸释放。
