Laboratory of Integrative Neuropharmacology, Department of Pharmaceutical Sciences, Thomas Jefferson University School of Pharmacy, 130 South 9th Street, Suite 1510, Philadelphia, PA 19107, USA.
Pharmacol Ther. 2010 Oct;128(1):37-60. doi: 10.1016/j.pharmthera.2010.05.003. Epub 2010 Jun 12.
Dopamine D(1)-like receptors consisting of D(1) and D(5) subtypes are intimately implicated in dopaminergic regulation of fundamental neurophysiologic processes such as mood, motivation, cognitive function, and motor activity. Upon stimulation, D(1)-like receptors initiate signal transduction cascades that are mediated through adenylyl cyclase or phosphoinositide metabolism, with subsequent enhancement of multiple downstream kinase cascades. The latter actions propagate and further amplify the receptor signals, thus predisposing D(1)-like receptors to multifaceted interactions with various other mediators and receptor systems. The adenylyl cyclase response to dopamine or selective D(1)-like receptor agonists is reliably associated with the D(1) subtype, while emerging evidence indicates that the phosphoinositide responses in native brain tissues may be preferentially mediated through stimulation of the D(5) receptor. Besides classic coupling of each receptor subtype to specific G proteins, additional biophysical models are advanced in attempts to account for differential subcellular distribution, heteromolecular oligomerization, and activity-dependent selectivity of the receptors. It is expected that significant advances in understanding of dopamine neurobiology will emerge from current and anticipated studies directed at uncovering the molecular mechanisms of D(5) coupling to phosphoinositide signaling, the structural features that might enhance pharmacological selectivity for D(5) versus D(1) subtypes, the mechanism by which dopamine may modulate phosphoinositide synthesis, the contributions of the various responsive signal mediators to D(1) or D(5) interactions with D(2)-like receptors, and the spectrum of dopaminergic functions that may be attributed to each receptor subtype and signaling pathway.
多巴胺 D1-样受体由 D1 和 D5 两种亚型组成，与多巴胺能调节情绪、动机、认知功能和运动活动等基本神经生理过程密切相关。受刺激后，D1-样受体启动信号转导级联反应，通过腺苷酸环化酶或磷酸肌醇代谢介导，随后增强多个下游激酶级联反应。后者的作用传播并进一步放大受体信号，从而使 D1-样受体与各种其他介质和受体系统发生多方面的相互作用。多巴胺或选择性 D1-样受体激动剂对腺苷酸环化酶的反应与 D1 亚型可靠相关，而新出现的证据表明，天然脑组织中的磷酸肌醇反应可能优先通过刺激 D5 受体介导。除了每种受体亚型与特定 G 蛋白的经典偶联外，还提出了其他生物物理模型，试图解释受体的亚细胞分布、异分子寡聚化和活性依赖性选择性的差异。预计从当前和预期的研究中，对 D5 与磷酸肌醇信号偶联的分子机制、可能增强 D5 相对于 D1 亚型药理学选择性的结构特征、多巴胺可能调节磷酸肌醇合成的机制、各种响应信号介质对 D1 或 D5 与 D2-样受体相互作用的贡献，以及可能归因于每种受体亚型和信号通路的多巴胺能功能谱的理解，将取得重大进展。
