Chen Jingyuan, Shen Changpeng, Meller Emanuel
Department of Psychiatry, New York University School of Medicine, 550 First Avenue MHL HN511, New York, NY 10016, USA.
Eur J Pharmacol. 2002 Oct 4;452(2):155-62. doi: 10.1016/s0014-2999(02)02297-5.
Mitogen-activated protein kinases (MAPKs), a family of signal transduction mediators important in a host of cellular activities, include the extracellular signal-regulated kinases Erk1 and Erk2. We determined whether 5-HT(1A) receptors activate Erk1/2 in rat brain in vivo, as they do in recombinant cell lines. In contrast to the effect in cells, the 5-HT(1A) receptor agonist 8-hydroxy-N,N-diproylaminotetralin (8-OH-DPAT) dose- and time-dependently decreased basal levels of phosphorylated Erk1/2 (phospho-Erk1/2) in rat hippocampus (ED(50) approximately 0.1 mg/kg, maximum approximately 90%) without altering total Erk1/2. The effects were kinase-specific, as 8-OH-DPAT did not modify phosphorylated or total levels of the MAPKs c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) and p38 MAPK. Moreover, 8-OH-DPAT did not modify phospho-Erk1/2 in striatum or frontal cortex. The effect of 8-OH-DPAT was blocked by pretreatment with the selective 5-HT(1A) receptor antagonists N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY 100635), 1-(2-methoxyphenyl)-4-(4-[2-phthalimido]butyl)piperazine (NAN-190) and 4-fluoro-N-(2-[4-(2-methoxyphenyl)1-piperazinyl]ethyl)-N-(2-pyridinyl)benzamide dihydrochloride (p-MPPF), but not by the weak partial agonist/antagonist 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8-azaspiro(4.5)decane-7,9-dione dihydrochloride (BMY 7378). Other 5-HT(1A) receptor agonists (buspirone, gepirone and ipsapirone) also reduced phospho-Erk1/2 levels in hippocampus. 8-OH-DPAT also reduced the levels of the upstream activator of Erk1/2, phosphorylated extracellular signal-regulated kinase kinase (phospho-MEK1/2), and at least one potential downstream target, the nuclear transcription factor phospho-Elk-1. The region- and kinase-specific effects suggest that the Erk1/2 signal transduction cascade is likely an important differential mediator of 5-HT(1A) receptor-regulated events in the central nervous system.
丝裂原活化蛋白激酶（MAPKs）是一类在许多细胞活动中起重要作用的信号转导介质，包括细胞外信号调节激酶Erk1和Erk2。我们确定5-HT(1A)受体在大鼠脑内是否像在重组细胞系中一样激活Erk1/2。与在细胞中的作用相反，5-HT(1A)受体激动剂8-羟基-N,N-二丙基氨基四氢萘（8-OH-DPAT）剂量和时间依赖性地降低大鼠海马中磷酸化Erk1/2（p-Erk1/2）的基础水平（半数有效剂量约为0.1mg/kg，最大降低约90%），而不改变总Erk1/2水平。这些作用具有激酶特异性，因为8-OH-DPAT不改变MAPKs c-Jun氨基末端激酶/应激激活蛋白激酶（JNK/SAPK）和p38 MAPK的磷酸化或总水平。此外，8-OH-DPAT不改变纹状体或额叶皮质中的p-Erk1/2。8-OH-DPAT的作用可被选择性5-HT(1A)受体拮抗剂N-[2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基]-N-2-吡啶基环己烷甲酰胺（WAY 100635）、1-(2-甲氧基苯基)-4-(4-[2-邻苯二甲酰亚胺基]丁基)哌嗪（NAN-190）和4-氟-N-(2-[4-(2-甲氧基苯基)1-哌嗪基]乙基)-N-(2-吡啶基)苯甲酰胺二盐酸盐（p-MPPF）预处理所阻断，但不能被弱部分激动剂/拮抗剂8-(2-[4-(2-甲氧基苯基)-1-哌嗪基]乙基)-8-氮杂螺(4.5)癸烷-7,9-二酮二盐酸盐（BMY 7378）阻断。其他5-HT(1A)受体激动剂（丁螺环酮、吉哌隆和伊沙匹隆）也降低海马中的p-Erk1/2水平。8-OH-DPAT还降低了Erk1/2的上游激活剂磷酸化细胞外信号调节激酶激酶（p-MEK1/2）的水平，以及至少一个潜在的下游靶点核转录因子磷酸化Elk-1的水平。区域和激酶特异性作用表明，Erk1/2信号转导级联可能是5-HT(1A)受体调节中枢神经系统事件的重要差异介质。
