Coupling of 5‐HT1A autoreceptors to inhibition of mitogen‐activated protein kinase activation via Gβγ subunit signaling
Coupling of 5‐HT1A autoreceptors to inhibition of mitogen‐activated protein kinase activation via Gβγ subunit signaling
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5-HT1A自身受体通过Gβγ亚基信号传导耦合抑制丝裂原激活蛋白激酶的激活
DOI：
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
P. Albert
中科院分区：
文献类型：
--
作者：
N. Kushwaha;P. Albert
5-HT 1A受体在突触前表达，作为突触能中缝神经元上的初级体树突自身受体，并在几个脑区域中突触后表达。在RN 46 A细胞中研究了5-HT 1A自身受体的信号传导，RN 46 A细胞是表达内源性5-HT 1A受体的多巴胺能中缝神经元的模型。在用野生型5-HT 1A受体稳定转染的未分化RN 46 A细胞中，5-HT 1A受体激活抑制毛喉素诱导的环磷酸腺苷（cAMP）形成（50%），增加[Ca 2 +]i，并诱导磷酸化p42/p44丝裂原激活蛋白激酶（MAPK）的新型抑制（高达60%）。在未转染或5-HT 1A转染的RN 46 A细胞分化后，激动剂介导的MAPK抑制增强。这些行动被阻断预处理百日咳毒素表明调解通过Gi/Go蛋白和钙反应被阻断蛋白激酶C（PKC）的预激活。在过表达G蛋白受体激酶2（GRK-CT）的Gβγ清除剂羧基末端结构域的细胞中，5-HT 1A受体激活抑制cAMP形成，但与钙动员和MAPK抑制的偶联被取消。检测了在第二个（i2：T149 A）或第三个胞内环（i3：T229 A/S253 G/T343 A）中含有PKC位点突变的5-HT 1A受体的活性。在相当的受体表达水平下，5-HT 1A i3突变体的信号传导与5-HT 1A野生型受体相似，而i2和四重（i2/i3）突变体未能与Gβγ介导的[Ca 2 +]i增加或MAPK抑制偶联，但与Gαi介导的cAMP抑制偶联。因此，5-HT 1A自身受体的i2-结构域对于与Gβγ亚基偶联及其随后的反应（例如钙动员和MAPK活性抑制）至关重要。
The 5‐HT1A receptor is expressed presynaptically as the primary somatodendritic autoreceptor on serotonergic raphe neurons, and postsynaptically in several brain regions. Signaling of the 5‐HT1A autoreceptor was studied in RN46A cells, a model of serotonergic raphe neurons that express endogenous 5‐HT1A receptors. In undifferentiated RN46A cells stably transfected with the wild‐type 5‐HT1A receptor, 5‐HT1A receptor activation inhibited forskolin‐induced cyclic adenosine monophosphate (cAMP) formation (by 50%), increased [Ca2+]i, and induced a novel inhibition (up to 60%) of phospho‐p42/p44‐mitogen‐activated protein kinase (MAPK). Upon differentiation of non‐transfected or 5‐HT1A‐transfected RN46A cells, agonist‐mediated inhibition of MAPK was enhanced. These actions were blocked by pretreatment with pertussis toxin indicating mediation via Gi/Go proteins and the calcium response was blocked by preactivation of protein kinase C (PKC). In cells overexpressing the Gβγ scavenger carboxyl‐terminal domain of G protein receptor kinase 2 (GRK‐CT), 5‐HT1A receptor activation inhibited cAMP formation, but coupling to calcium mobilization and inhibition of MAPK was abolished. The activity of 5‐HT1A receptors containing mutations of PKC sites in the second (i2: T149A) or third intracellular loop (i3: T229A/S253G/T343A) was tested. At comparable levels of receptor expression, the signaling of the 5‐HT1A i3 mutant was similar to the 5‐HT1A wild‐type receptor, while the i2 and quadruple (i2/i3) mutants failed to couple to Gβγ‐mediated increase in [Ca2+]i or inhibition of MAPK, but did couple to Gαi‐mediated inhibition of cAMP. Thus, the i2‐domain of the 5‐HT1A autoreceptor is crucial for coupling to Gβγ subunits and their subsequent responses (e.g. calcium mobilization and inhibition of MAPK activity).
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DOI：
10.1016/s0021-9258(17)37587-7
发表时间：
1994-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
W. Koch;B. Hawes;James Inglese;L. Luttrell;R. Lefkowitz
通讯作者：
W. Koch;B. Hawes;James Inglese;L. Luttrell;R. Lefkowitz
影响因子：
2.1
作者：
Luttrell, LM
通讯作者：
Luttrell, LM
影响因子：
2.5
作者：
Bayliss, DA;Li, YW;Talley, EM
通讯作者：
Talley, EM
突触后 5-羟色胺 1A 受体缺乏明显的受体储备，与大鼠海马膜中的腺苷酸环化酶活性呈负相关。
影响因子：
3.6
作者：
Yocca,FD;Iben,L;Meller,E
通讯作者：
Meller,E
DOI：
10.1016/s0021-9258(19)39437-2
发表时间：
1990-04
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Paul R. Albert;Qun-Yong Zhou;H. V. Tol;J. Bunzow;O. Civelli
通讯作者：
Paul R. Albert;Qun-Yong Zhou;H. V. Tol;J. Bunzow;O. Civelli