Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors
Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors
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DOI：
10.1007/s00210-008-0378-4
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发表时间：
2009-05-01
影响因子：
3.6
通讯作者：
Fitzgerald, Lawrence W.
中科院分区：
文献类型：
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作者：
Knauer, Christopher S.;Campbell, Jeffrey E.;Fitzgerald, Lawrence W.
已知2型5-羟色胺（5-HT 2）受体亚家族与磷酸肌醇水解（PI）和随后的细胞内Ca 2+的动员以及花生四烯酸（AA）的释放偶联。5-HT 2介导的丝裂原活化蛋白激酶（MAPK）或细胞外信号调节激酶（ERK 1/2）信号的激活知之甚少。本研究测量了5-HT激动剂在表达重组人5-HT 2A、5-HT 2B和5-HT 2C（ISV）受体的非神经元细胞中激活ERK 2的相对功效和效力。5-HT激动剂通过所有三种5-HT 2亚型刺激ERK 2活性。这些激动剂影响ERK 2活性与PI蓄积或Ca 2+动员的效力或相对效力无有意义的差异，表明这些途径可能顺序相关。事实上，ERK 2活性对PKC抑制和钙螯合非常敏感，对酪氨酸激酶和PI-3-激酶抑制不敏感。5-HT 2受体通过顺序的PI水解和Ca 2+动员有效地偶联到MAPK活化。这种配置文件不同于报告的“激动剂直接贩运的受体刺激”之间的PI/Ca 2+和AA途径激活的5-HT 2受体。
The type 2 serotonin (5-HT2) receptor subfamily is known to couple to phosphoinositide hydrolysis (PI) and the subsequent mobilization of intracellular Ca2+, as well as the release of arachidonic acid (AA). Less is known of 5-HT2-mediated activation of the mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase (ERK1/2) signaling. The present study measured the relative efficacies and potencies of 5-HT agonists to activate ERK2 in non-neuronal cells expressing recombinant human 5-HT2A, 5-HT2B, and 5-HT2C(ISV) receptors. 5-HT agonists stimulated ERK2 activity via all three 5-HT2 subtypes. There were no meaningful differences in the potencies or relative efficacies of these agonists to affect ERK2 activity vs. PI accumulation or Ca2+ mobilization, suggesting that these pathways may be sequentially linked. Indeed, ERK2 activity was very sensitive to PKC inhibition and calcium chelation and insensitive to tyrosine kinase and PI-3-kinase inhibition. 5-HT2 receptors efficiently couple to MAPK activation via sequential PI hydrolysis, and Ca2+ mobilization. This profile differs from reports of "agonist-directed trafficking of receptor stimulus" between PI/Ca2+ and AA pathways activated by 5-HT2 receptors.