Click on each of the dopamine receptor families below to see the signaling pathways activated by receptors in that family. Click on DARPP-32 to view the phosphorylation sites on DARPP-32 with the respective kinases.
Dopamine (DA) is the dominate catecholamine neurotransmitter in the brain. It participates in a number of functions such as locomotion, memory, emotional and motivated behaviors, and neuroendocrine regulation. DA levels have been implicated in numerous neurological and psychiatric disorders including Parkinson’s disease, Huntington's disease, schizophrenia, bipolar disorder, attention deficit hyperactivity disorder, and Tourette's syndrome.
DA exerts its effects through five G protein-coupled receptors that are divided into two families based on structure and biological response: D1- and D2-like receptor families. The D1-like receptors, Dopamine D1 Receptor/DRD1 and Dopamine D5 Receptor/DRD5, share 80% amino acid (aa) sequence homology in their transmembrane domains, while the D2-like receptors, Dopamine D2 Receptor/DRD2, Dopamine D3 Receptor/DRD3, and Dopamine D4 Receptor/DRD4, are less homologous. The transmembrane regions of the D2 receptor share 75% and 53% aa sequence homology with the transmembrane domains of the D3 and D4 receptors, respectively. The D1 and D2 receptors are the most abundant dopamine receptor subtypes in the brain and exhibit broad expression patterns. The highest expression levels of the D1 receptor are observed in the caudate-putamen, nucleus accumbens, substantia nigra, olfactory bulb, amygdala, and frontal cortex. The highest levels of the D2 receptor are found in the caudate-putamen, nucleus accumbens, olfactory tubercle, substantia nigra, ventral tegmental area, hypothalamus, septum, amygdala, hippocampus, and cortical areas.
Dopamine receptors are traditionally viewed as signaling through the cAMP-dependent signaling pathway. D1-like receptors, which are primarily coupled to the heterotrimeric G proteins G alpha s and G alpha olf, stimulate Adenylyl Cyclase activity, cAMP production, and Protein Kinase A activation. This results in the phosphorylation and activation of a variety of substrates including Dopamine- and cAMP-Regulated Phosphoprotein, Mr 32 kDa (DARPP-32). DARPP-32, when phosphorylated on Thr34, is a potent inhibitor of Protein Phosphatase 1 (PP1). By inhibiting PP1, many downstream physiological effectors, including various neurotransmitter receptors, ion channels and pumps, and transcription factors, are phosphorylated and activated. In contrast, D2-like receptors negatively regulate Adenylyl Cyclase activation. These receptors are coupled to the pertussis toxin-sensitive, heterotrimeric G proteins G alpha i and G alpha o, which inhibit Adenylyl Cyclase, cAMP production, Protein Kinase A activation, and phosphorylation of DARPP-32 at Thr34. D2-like receptors also activate the protein phosphatase Calcineurin, which dephosphorylates DARPP-32 at Thr34.
Dopamine receptors also exert some of their biological effects through alternative signaling pathways that do not involve cAMP. For instance, dopamine receptors can activate PLC-mediated signaling. Additionally, both D1- and D2-like receptors can activate MAPK signaling; however, both receptor families require interaction with other surface proteins. D1-like receptor-mediated ERK activation involves an interaction with the NMDA glutamate receptor, which increases intracellular calcium levels and activates MAPK signaling. D2-like receptor-mediated MAPK signaling requires the transactivation of receptor tyrosine kinases. It has also been suggested that the D2 receptor can be internalized in a β-Arrestin/Dynamin-dependent manner and that the D2 receptor/β-Arrestin complex can activate MAPK signaling.