Differential coupling of serotonin 5-HT1A and 5-HT1B receptors to activation of ERK2 and inhibition of adenylyl cyclase in transfected CHO cells
Differential coupling of serotonin 5-HT1A and 5-HT1B receptors to activation of ERK2 and inhibition of adenylyl cyclase in transfected CHO cells
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DOI：
10.1046/j.1471-4159.1999.0730162.x
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发表时间：
1999-07-01
影响因子：
4.7
通讯作者：
Cowen, DS
中科院分区：
文献类型：
--
作者：
Mendez, J;Kadia, TM;Cowen, DS
尽管5-HT1受体亚型具有不同的结构和药理学，但尚不清楚它们是否也表现出与细胞信号耦合的差异。我们试图直接比较5-HT1A和5-HT1B受体与腺苷酸环化酶和丝裂原活化蛋白激酶ERK2（细胞外信号调节激酶-2）的偶联。我们发现5-HT1B受体比5-HT1A受体更能激活ERK2和抑制腺苷酸环化酶。在低密度表达内源性5-HT1B受体的未转染细胞中，5-HT刺激ERK2活性最大增加4倍，在表达230 fmol 5-HT1B受体/mg膜蛋白的转染细胞中，ERK2活性最大增加13倍。相比之下，在300 fmol/mg膜蛋白表达受体的转染细胞中，5-HT1A受体的激活仅刺激ERK2的2.8倍最大激活，但在3000 fmol/mg膜蛋白表达受体的细胞中，其活性确实刺激了12倍的增加。同样，5-HT1A受体，而不是5-HT1B受体，只有在高密度表达时，才能显著抑制福斯克林刺激的环AMP积累。这些发现表明，尽管5-HT1A和5-HT1B受体已被证明与G(i)类的G蛋白偶联，但它们与ERK2和腺苷酸环化酶的偶联表现出差异。
Although the subtypes of serotonin 5-HT1 receptors have distinct structure and pharmacology, it has not been clear if they also exhibit differences in coupling to cellular signals. We have sought to compare directly the coupling of 5-HT1A and 5-HT1B receptors to adenylyl cyclase and to the mitogen-activated protein kinase ERK2 (extracellular signal-regulated kinase-2). We found that 5-HT1B receptors couple better to activation of ERK2 and inhibition of adenylyl cyclase than do 5-HT1A receptors. 5-HT stimulated a maximal fourfold increase in ERK2 activity in nontransfected cells that express endogenous 5-HT1B receptors at a very low density and a maximal 13-fold increase in transfected cells expressing 230 fmol of 5-HT1B receptor/mg of membrane protein. In contrast, activation of 5-HT1A receptors stimulated only a 2.8-fold maximal activation of ERK2 in transfected cells expressing receptors at 300 fmol/mg of membrane protein but did stimulate a 12-fold increase in activity in cells expressing receptors at 3,000 fmol/mg of membrane protein. Similarly, 5-HT1A, but not 5-HT1B, receptors were found to cause significant inhibition of forskolin-stimulated cyclic AMP accumulation only when expressed at high densities. These findings demonstrate that although both 5-HT1A and 5-HT1B receptors have been shown to couple to G proteins of the G(i) class, they exhibit differences in coupling to ERK2 and adenylyl cyclase.