Functional selectivity of D2 receptor ligands in a Chinese hamster ovary hD2L cell line:: Evidence for induction of ligand-specific receptor states
Functional selectivity of D2 receptor ligands in a Chinese hamster ovary hD2L cell line:: Evidence for induction of ligand-specific receptor states
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DOI：
10.1124/mol.66.1.97
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发表时间：
2004-07-01
影响因子：
3.6
通讯作者：
Mailman, RB
中科院分区：
文献类型：
--
作者：
Gay, EA;Urban, JD;Mailman, RB
现在有几个单一的G蛋白偶联受体的例子，特定的激动剂与其结合会对相关的信号通路产生不同的影响。多巴胺D-2受体具有特殊的重要性，因为功能通路的选择性激活在体外和原位都已被证明。为此，本工作利用三个不同的功能终点表征了一系列刚性D-2激动剂在转染人D-2L受体的中国仓鼠卵巢细胞中的作用：抑制cAMP合成，刺激丝裂原活化蛋白(MAP)激酶磷酸化，激活G蛋白偶联的内向整流钾通道(GIRKs)。在该系统中，S-丙基去甲吗啡、R-丙基去甲吗啡、二氢呋喃、地奈普林和地诺可抑制福司可林刺激的腺苷环化酶活性，其抑制程度与典型的D-2激动剂奎比罗(QP)相同。药效排序如下：RNPA远大于QP=DNX>；SNPA>；DHX=DNX。DHX、DNX、DNX和RNPA对MAP激酶磷酸化的作用与QP相似，而SNPA为部分激动剂。MAP激酶磷酸化的效价顺序为RNPA远大于qp=dnx>；dhx>；dns>；SNPA。DNX对GIRK通道的激活程度与QP相同，DHX和DNS为部分激动剂，RNPA和SNPA对GIRK通道无明显激活作用。这些发现表明，DHX、DNS、RNPA和SNPA在HD(2L)受体上具有非典型的功能特性，并显示出不同的功能选择性模式。我们假设这种功能选择性可能是D-2L受体的特定构象的配体诱导的结果，该配体仅激活选定的信号通路。
There are now several examples of single G protein-coupled receptors to which binding of specific agonists causes differential effects on the associated signaling pathways. The dopamine D-2 receptor is of special importance because the selective activation of functional pathways has been shown both in vitro and in situ. For this reason, the present work characterized a series of rigid D-2 agonists in Chinese hamster ovary cells transfected with the human D-2L receptor using three distinct functional endpoints: inhibition of cAMP synthesis, stimulation of mitogen-activated protein ( MAP) kinase phosphorylation, and activation of G protein-coupled inwardly rectifying potassium channels (GIRKs). In this system, S-propylnorapomorphine (SNPA), R-propylnorapomorphine (RNPA), dihydrexidine (DHX), dinapsoline (DNS), and dinoxyline (DNX) all inhibited forskolin-stimulated adenylate cyclase activity to the same extent as the prototypical D-2 agonist quinpirole (QP). The rank order of potency was the following: RNPA much greater than QP = DNX > SNPA > DHX = DNS. For MAP kinase phosphorylation, DHX, DNS, DNX, and RNPA had efficacy similar to QP, whereas SNPA was a partial agonist. The rank order of potency for MAP kinase phosphorylation was RNPA much greater than QP = DNX > DHX > DNS > SNPA. DNX activated GIRK channels to the same extent as QP, whereas DHX and DNS were partial agonists, and RNPA and SNPA caused no appreciable activation. These findings indicate that DHX, DNS, RNPA, and SNPA have atypical functional properties at the hD(2L) receptor and display different patterns of functional selectivity. We hypothesize that this functional selectivity may be a result of ligand induction of specific conformations of the D-2L receptor that activate only selected signaling pathways.