Nicotine activity on dopaminergic neurons

Nicotine is an alkaloid found in tobacco plants. It is a substance that acts as a stimulant in humans and is one of the main factors responsible for tobacco dependence. When nicotine enters the body, it is distributed quickly through the bloodstream, and it can cross the blood-brain barrier to enter the central nervous system (CNS). It binds to two main types of nicotinic acetylcholine receptors: the ganglion type and the CNS type. In dopaminergic neurons in the CNS, nicotine binds to the CNS-type nicotinic acetylcholine receptors. The main type of CNS receptor is composed of alpha 4 beta 2 (CHRNA4, CHRNB2) subunits. It has been shown that alpha 6, alpha 5, and beta 3 can also be in the receptor complex to modulate binding sensitivity. By binding to the receptor, nicotine causes cell depolarization and release of dopamine from the cell through the SNARE complex. Dopamine then binds to dopamine receptors (DRD2, DRD3, DRD4) on dopaminergic terminals and activates Gi alpha (GNAI1), initiating a feedback loop to inhibit dopamine release. One of the key players mediating dopamine signaling is PPP1R1B (also called DARPP-32, dopamine and cyclic AMP-regulated phospho-protein). PPP1R1B is a bifunctional signal transduction molecule which, by distinct mechanisms, inhibits either a serine/threonine kinase (PPKACA or PKA) or a serine/threonine phosphatase (PPP1CA or protein phosphatase 1). When PPP1R1B is phosphorylated by PPKACA at threonine 34, it is an inhibitor of protein phosphatase 1 (PPP1CA), which inhibits dopamine secretion through the SNARE complex. When PPP1R1B is phosphorylated by CDK5 at threonine 75, it is converted to an inhibitor of PPKACA. Binding of dopamine to D2-like dopamine receptors leads to inhibition of adenylate cyclase (ADCY2) via G-protein GNAI1, and decreases PKA-stimulated phosphorylation of DARPP-32 at Thr34. This, in turn, relieves the inhibition of protein phosphatase 1 (PPP1CA), and inhibits further dopamine release. Sources: [http://www.pharmgkb.org/do/serve?objId=PA162355621&objCls=Pathway PharmGKB:Nicotine in Dopaminergic Neurons], [http://en.wikipedia.org/wiki/Nicotine Wikipedia:Nicotine]

尼古丁是一种存在于烟草植物中的生物碱。该物质在人体内充当兴奋剂，并是导致烟草依赖的主要因素之一。尼古丁进入人体后，能迅速通过血液循环系统分布，并可穿越血脑屏障进入中枢神经系统（CNS）。它主要与两种类型的烟碱型乙酰胆碱受体结合：神经节型和中枢型。在中枢神经系统的多巴胺能神经元中，尼古丁与中枢型烟碱型乙酰胆碱受体结合。中枢型受体的主要类型由α4β2（CHRNA4，CHRNB2）亚基组成。研究表明，α6、α5和β3也可以存在于受体复合体中，以调节结合敏感性。通过结合受体，尼古丁引起细胞去极化和通过SNARE复合体释放多巴胺。随后，多巴胺与多巴胺受体（DRD2、DRD3、DRD4）结合，激活Gi alpha（GNAI1），启动反馈循环以抑制多巴胺释放。在调节多巴胺信号传导的关键因素中，PPP1R1B（亦称为DARPP-32，多巴胺和环磷酸腺苷调节的磷酸蛋白）起着重要作用。PPP1R1B是一种双功能信号转导分子，通过不同的机制抑制丝氨酸/苏氨酸激酶（PPKACA或PKA）或丝氨酸/苏氨酸磷酸酶（PPP1CA或蛋白磷酸酶1）。当PPP1R1B在苏氨酸34位被PPKACA磷酸化时，它作为蛋白磷酸酶1（PPP1CA）的抑制剂，通过SNARE复合体抑制多巴胺分泌。当PPP1R1B在苏氨酸75位被CDK5磷酸化时，它转变为PPKACA的抑制剂。多巴胺与D2样多巴胺受体的结合通过G蛋白GNAI1抑制腺苷酸环化酶（ADCY2），并减少PKA刺激下DARPP-32在苏氨酸34位的磷酸化。这反过来又缓解了蛋白磷酸酶1（PPP1CA）的抑制，并抑制了进一步的多巴胺释放。资料来源：[http://www.pharmgkb.org/do/serve?objId=PA162355621&objCls=Pathway PharmGKB:Nicotine in Dopaminergic Neurons]，[http://en.wikipedia.org/wiki/Nicotine Wikipedia:Nicotine]