Dopamine Receptors Philip G. Strange1 and Kim Neve2 History 1School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AJ, UK It was not until the late 1950s that dopamine was recognized Email: [email protected] as a neurotransmitter in its own right, but the demonstration of its non-uniform distribution in the brain, distinct from the 2VA Medical Center and Department of Behavioral Neuroscience, distribution of noradrenaline, suggested a specific functional Oregon Health & Science University, Portland, OR 97239, USA role for dopamine.1 Interest in dopamine was intensified by the Email: [email protected] realization that dopamine had an important role in the patho- Professor Philip Strange has worked on the structure and genesis or drug treatment of certain neurological disorders, function of G protein-coupled receptors for many years. e.g. Parkinson’s disease and schizophrenia.2,3 This led to much A major focus of his work has been the receptors for the research on the sites of action of dopamine and the dopamine neurotransmitter dopamine, with particular emphasis on their receptors (Box 1). One milestone was the suggestion by Cools role as targets for drugs and understanding the mechanisms of agonism and inverse agonism at these receptors. and van Rossum, based on anatomical, electrophysiological and pharmacological studies, that there might be more than Professor Kim Neve has studied dopamine receptors for most one kind of receptor for dopamine in the brain.4 Biochemical of his scientific career, with an emphasis on relating structural studies on dopamine receptors in the 1970s based on second features of the receptors to specific functions and assessing how messenger assays (e.g. stimulation of cAMP production and receptor responsiveness is altered by denervation or prolonged ligand binding assays) supported the idea, and it was given a treatment with agonists. firm foundation by Kebabian and Calne in their 1979 review.5 They extended an earlier suggestion by Spano et al,6 and pro- posed that there were two classes of dopamine receptor, D1 and D2, with different biochemical and pharmacological properties, mediating different physiological functions. The properties of these two subtypes are summarized in Table 1. Selective ago- nists and antagonists exist to define the two subtypes in func- tional assays and some of these are shown in Table 1. Both the D1 and D2 subtypes are G protein-coupled receptors (GPCRs), yet different G proteins and effectors are involved in their signaling pathways (Figure 1, Table 1). Although there were some indications of further heterogene- ity of these dopamine receptor subtypes in biochemical stud- ies, it was not until the late 1980s that the true extent of this was revealed with the application of gene cloning techniques. These studies have shown that there are at least five dopamine receptors (D1-D5) that may be divided into two subfamilies 7,8 whose properties resemble the original D1 and D2 receptors. The 1D -like receptor family, which comprises D1 and D5, cor- responds to the original D1 receptors whilst the D2-like receptor family (D , D and D receptors) corresponds to the original Contents 2 3 4 D2 receptors. A selection of the key properties of the receptor History ..................................................................................................................................1 subtypes are summarized in Tables 2 and 3. Properties of the Dopamine Receptor Subtypes ..........................2 Future Directions ........................................................................................................6 In subsequent discussion we refer to receptor subtypes defined References ........................................................................................................................8 from cloned genes as D1, D2, D3, D4, D5, and where only the Dopamine Compounds .........................................................................................9 subfamily of receptor has been defined pharmacologically we use the D1-like and D2-like nomenclature. Tocris Bioscience Scientific Review Series www.tocris.com | 1 Tocris Bioscience Scientific Review Series Box 1: Dopamine receptor products Box 1 | Dopamine synthesis and metabolism in the human population with variants containing different 16,17 length insertions in I3. In some cases, these D2-like receptor NO2 O variants may have differential abilities to couple to or activate 18,19 O N G proteins, and may also exhibit slightly different pharma- H cological properties.16,20,21 Lines of mice have been developed in HO NH2 which the I3 insertion that produces the long D2 receptor vari- OH ant (D ) is deleted, resulting in the expression of only the short HO 2L OH variant (D2S). Characterization of these mice suggests that the splice variants are not fully interchangeable; some D receptor Dopamine (3548) NPEC-caged-dopamine (3992) 2 22-24 Endogenous dopamine Caged version of dopamine responses are not observed in mice that express only D2S. receptor agonist The variants of the D4 receptor have not been found to exhibit any substantive differences in agonist signaling or in coupling SO2Me to G proteins.25 HO CO H H 2 The individual properties of the different subtypes were ini- N NH2 HO tially probed by expressing the receptors in recombinant cells and examining the localization of the subtypes at the mRNA L-DOPA (3788) OSU 6162 (2599) and protein level. More recently, the use of subtype-selective Dopamine precursor Dopamine stabilizer drugs and transgenic mice with one or more receptor subtypes genetically deleted has enabled further study of these receptors. Properties of the Dopamine Receptor Subtypes Individual receptor properties The dopamine receptor subtypes exhibit different proper- Common receptor properties ties in terms of their pharmacological profile, localization, Analysis of the amino acid sequences of the dopamine receptor and mechanism of action; these differences will be briefly subtypes has shown that significant homologies exist among summarized below. the subtypes, with the greatest being found between members 7,8 of either subfamily. Each receptor has been shown to contain D1-like receptors seven stretches of amino acids that are hydrophobic and long Both the D1 and D5 receptors show pharmacological properties enough to span the membrane. It seems therefore that each similar to those of the original pharmacologically defined 1D of the dopamine receptors conforms to the general structural receptor, that is, a high affinity for the benzazepine ligands SCH model for a GPCR,9-11 with an extracellular amino terminus 23390, SCH 39166, and SKF 83566, which are selective antago- and seven putative membrane spanning α-helices linked by nists for these subtypes. Although not as selective for D1 over intracellular and extracellular protein loops (Figure 2). One or D2 as the benzazepine antagonists, LE 300 is a potent D1-like more potential sites for glycosylation are found on the amino antagonist that is useful because it is structurally distinct terminus and second extracellular loop. The helices are bun- from the benzazepines. Thioxanthines such as flupentixol and dled together in the membrane to form the ligand binding site (Figure 2); some information is available on the residues that Figure 1 | Regulation of adenylyl cyclase by D and D dopamine 11,12 1 2 make contact with ligands. There is an intracellular carboxyl receptors terminus, probably bearing a palmitoyl group, which may form a further link to the membrane. The 1D -like receptors have Dopamine Dopamine short third intracellular loops and long carboxyl terminal tails, whereas the D2-like receptors have long third intracellular loops D -like receptor D -like receptor and short carboxyl terminal tails. This provides a structural 1 2 basis for the division of the receptors into two subfamilies but is also likely to have a functional significance, possibly related AC to the specificity of receptor/G protein interaction. βγ + – βγ Gαs Gαi/o ATP The third intracellular loop, termed ‘I3’, is important for the cAMP interaction of the receptor and G protein. For the D2-like receptors, variants of the subtypes exist based on this loop. For example, there are short and long splice variants of the D2 and D3 receptors with the long forms having an insertion (29 amino 13,14 acids for the long D2, D2L) in this loop. Polymorphic vari- The diagram shows the effects of dopamine to stimulate or inhibit ants of the D2 receptor have been described with single amino adenylyl cyclase (AC) via the D1-like receptor and G protein Gαs or 15 the D -like receptor and G protein Gα , respectively. acid changes in I3. The D4 receptor is highly polymorphic 2 i/o 2 | DopamiNE RECEPTORS Table 1 | Dopamine receptor subtypes defined from physiological, pharmacological, and biochemical studies D1-like Receptors D2-like Receptors Physiological Functions Aspects of motor and cognitive function (brain), Aspects of motor function and behavior (brain), control of prolactin and cardiovascular function α-MSH secretion from pituitary, cardiovascular function Biochemical Responses Adenylyl cyclase↑ Adenylyl cyclase↓ Phospholipase C↑ K+ channel activity↑ Ca2+ channel activity↓ GSK-3b↑ Localization Caudate nucleus, putamen, nucleus accumbens, Caudate nucleus, putamen, nucleus accumbens, olfactory tubercle, olfactory tubercle, cerebral cortex, cardiovascular cerebral cortex, anterior and neurointermediate lobes of pituitary gland, system cardiovascular system