Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo.
Serotonin, but not N-methyltryptamines, activates the serotonin 2A receptor via a ß-arrestin2/Src/Akt signaling complex in vivo.
复制标题
5-羟色胺，但不是N-甲基丁胺，通过体内的ß-arrestin2/src/akt信号传导复合物激活5-羟色胺2A受体。
DOI：
10.1523/jneurosci.1665-10.2010
复制
发表时间：
2010-10-06
期刊：
影响因子：
--
通讯作者：
Bohn LM
中科院分区：
文献类型：
--
作者：
Schmid CL;Bohn LM
致幻剂通过激活5-羟色胺2A受体（5-HT2AR）介导许多精神活性作用。虽然5-羟色胺是同源的内源性神经递质，不被认为是致幻物质，但5-羟色胺的代谢物也对5-HT2AR具有高亲和力，可以诱导人类产生幻觉。在这里，我们报道了5 -羟色胺与精神活性n -甲基色胺的不同之处在于其参与额叶皮层β阻滞2介导的信号级联的能力。血清素和5-羟- l -色氨酸（5-HTP）诱导野生型（WT）小鼠的头抽搐反应，这是5-HT2AR激活的行为代理。βarrestin2基因敲除（βarr2-KO）小鼠的反应大大减弱，直到剂量升高，此时βarr2-KO小鼠表现出超过WT小鼠的头抽搐反应。直接给药n -甲基色胺在βarr2-KO小鼠中也产生更大的反应。此外，在βarr2-KO小鼠中，n -甲基转移酶的抑制阻断了5-羟色胺诱导的头抽搐，这表明n -甲基trypatines而不是5-羟色胺主要介导了这种反应。生化研究表明，5 -羟色胺通过激活βarrestin2/PI3-K/Src/Akt级联刺激额叶皮层和初级皮质神经元的Akt磷酸化，而n -甲基色胺则没有。此外，这种级联的任何组成部分的破坏都可以防止5-羟色胺，而不是n -甲基色胺引起的头部抽搐。我们认为5-HT2AR信号的分化依赖于神经递质和β抑制蛋白2。这一激动剂导向的5-HT2AR信号在体内的证明，可能会显著影响药物研发工作，以治疗幻觉作为病因的疾病，如精神分裂症，或表现为治疗的副作用，如抑郁症。
Hallucinogens mediate many of their psychoactive effects by activating serotonin 2A receptors (5-HT2AR). While serotonin is the cognate endogenous neurotransmitter and is not considered hallucinogenic, metabolites of serotonin also have high affinity at 5-HT2AR and can induce hallucinations in humans. Here we report that serotonin differs from the psychoactive N-methyltryptamines by its ability to engage a βarrestin2-mediated signaling cascade in the frontal cortex. Serotonin and 5-hydroxy-L-tryptophan (5-HTP) induce a head twitch response in wild-type (WT) mice which is a behavioral proxy for 5-HT2AR activation. The response in βarrestin2 knockout (βarr2-KO) mice is greatly attenuated until the doses are elevated, at which point, βarr2-KO mice display a head twitch response that can exceed that of WT mice. Direct administration of N-methyltryptamines also produces a greater response in βarr2-KO mice. Moreover, the inhibition of N-methyltransferase blocks 5-HTP-induced head twitches in βarr2-KO mice indicating that N-methyltrypatmines, rather than serotonin, primarily mediate this response. Biochemical studies demonstrate that serotonin stimulates Akt phosphorylation in the frontal cortex and in primary cortical neurons through the activation of a βarrestin2/PI3-K/Src/Akt cascade, while N-methyltryptamines do not. Further, disruption of any of the components of this cascade prevents 5-HTP-, but not N-methyltryptamine-induced, head twitches. We propose that there is a bifurcation of 5-HT2AR signaling that is neurotransmitter- and βarrestin2-dependent. This demonstration of agonist-directed 5-HT2AR signaling in vivo, may significantly impact drug discovery efforts for the treatment of disorders wherein hallucinations are part of the etiology, such as schizophrenia, or manifest as side effects of treatment, such as depression.