Dopamine Receptors

K A Neve, Portland Veterans Affairs Medical Center, Portland, OR, USA

ã 2013 Elsevier Inc. All rights reserved.

Glossary Receptor A protein, usually associated with the cell

Affinity The term for how tightly a drug binds to membrane, that binds a neurotransmitter or hormone and
a receptor, expressed as the concentration of drug initiates a biological response.
that occupies half of the available receptors. High Second messenger A chemical signal elicited by an
affinity means that a drug will bind at very low activated receptor that transmits information within a cell.
concentrations. The extracellular neurotransmitter is the first messenger,
Agonist A drug that binds to and activates a receptor. and whereas some receptors transduce information
Dopamine is the endogenous agonist for dopamine about the neurotransmitter concentration into an
receptors. electrical response, other receptors convert that
Antagonist A drug that binds to a receptor information into altered abundance of an intracellular
without activating it and, thus, prevents the binding of second messenger such as cyclic adenosine
an agonist. monophosphate (AMP).

Introduction D1-Like and D2-Like Receptor Subfamilies

Prior to the molecular cloning of dopamine receptors, they
Nobel prize-winning work by Carlsson and colleagues in
were divided into D1 and D2 subtypes on the basis of several
1958 first demonstrated that dopamine is a neurotransmitter,
criteria. D1 and D2 receptors have distinct pharmacological
rather than being only an intermediate step in the synthesis
profiles; in particular, D2 receptors have high affinity for ben-
of norepinephrine, and a neurotransmitter that plays an
zamide and butyrophenone antagonists such as sulpiride and
important role in regulating motor behavior. The first phar-
spiperone, respectively, while D1 receptors have high affinity
macological evidence for the existence of specialized receptors
for benzazepine antagonists such as SCH23390. D1 receptors
for dopamine was obtained 5 years later, but it was not until
stimulate adenylate cyclase and cyclic AMP accumulation,
1972 that the identification of dopamine-stimulated adeny-
while D2 receptors inhibit the enzyme. Furthermore, the D1
late cyclase, the enzyme that converts adenosine triphosphate
and D2 receptors are physically distinct. For example, there are
(ATP) into the second messenger cyclic adenosine monopho-
tissues such as the anterior and intermediate pituitary gland
sphate (AMP), made possible the biochemical characteriza-
that have an abundance of D2 receptors but no D1 receptors.
tion of a dopamine receptor. Later that decade, further
Finally, it is possible to cause selective damage to cell bodies in
pharmacological and biochemical characterization of dopa-
the substantia nigra or in the neostriatum of the rat brain,
mine receptors, including their division into D1 and D2
using lesions that spare axons and axon terminals, and with
subtypes, was made possible by the development of radio-
these lesions to cause a preferential reduction in the abundance
isotopically labeled ligands, or radioligands, that bind to
of D2 receptors (substantia nigra) or D1 receptors (neostria-
dopamine receptors with high affinity and selectivity. What
tum), thus demonstrating the differential localization of the
might be considered the modern era of dopamine receptor
subtypes on cell bodies and axon terminals in these brain
research began in 1988 with the determination of the DNA
regions. The molecular cloning of additional subtypes of dopa-
sequence and predicted protein sequence of the D2 dopa-
mine receptors revealed the existence of two receptor subfami-
mine receptor and the subsequent identification of additional
lies, in each of which the subtypes share D1-like or D2-like
dopamine receptor subtypes.
characteristics.

Molecular Cloning of Dopamine Receptor Subtypes

Dopamine Receptor Subtypes
Following the cloning of DNA encoding receptors determined
Virtually all neurotransmitters and hormones activate multiple to be identical to the pharmacologically characterized D1 and
receptor subtypes – distinct classes of receptors that share D2 receptors, several additional subtypes were identified in
relatively high affinity for a single neurotransmitter but that 1990–91. DNA sequence information was a new tool for clas-
differ in sequence, affinity for drugs, signaling, and distribu- sification of receptors, in that receptors belonging to the same
tion. It is common for the distribution of receptor subtypes to subfamily are more similar in DNA and protein sequence.
overlap, so that one organ or brain region may have multiple Thus, there are many amino acids that are common in D1
receptor subtypes for any neurotransmitter or hormone that and D5 receptors (Figure 1(a)), but fewer that are shared
is present. among all the dopamine receptor subtypes (Figure 1(b)).

169
170 Signaling | Dopamine Receptors

S D GN A T S L A
ST N LT R
M SP E
MA T T
D P I
G D
GT K
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L A
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V H D TQ PF
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D G G L L C D

V SF E IA CF S Q T RS ILP
F NS
R A IN PV Y
T LI K AV VW SI A I LN
C DFT
CA W A SF I
L F MP I DF V SS P F F VFV
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I LL AV TS C FS I V CC GF
L LV A TLS VF W
LT S DL LI S PI Y M G NA
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T N G L A V V CL I AV LS V LSS
L S I LI S T
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L V KL P AR L H A R FA RSS T
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PD M I V TC L K M D E P HT C N T K
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GLH ST P DS PA K P E K NGH A K L
(b) H
C

Figure 1 Predicted amino acid sequence and membrane-spanning segments of the D1 (a) and D2 (b) dopamine receptor subtypes. The figure is
oriented so that the extracellular regions of each receptor are above the shaded transmembrane helices and the intracellular regions are below.
Amino acids colored red in panel (a) are shared between D1 and D5 receptors, whereas amino acids colored purple in panel (b) are shared among
all of the dopamine receptor subtypes.
 Signaling | Dopamine Receptors 171

D1 and D5 receptors are both D1-like receptors, whereas D2, of D1-like or D2-like receptor stimulation. There are numerous
D3, and D4 receptors belong to the D2-like receptor subfamily commercially available potent and selective D2-like receptor
in terms of sequence identity and affinity for drugs. agonists such as quinpirole and 7-OH DPAT, and antagonists
such as spiperone and nemonapride (YM-09151-2). Although
there are fewer D1-like receptor-selective drugs, the selective
Structural Characteristics of Dopamine Receptors benzazepine antagonist SCH23390 and agonists such as
SKF38393 and 6-chloro-APB (SKF82958) have been used to
Most hormone and neurotransmitter receptors are integral demonstrate that blockade or stimulation of D1-like receptors
membrane proteins that span the cell membrane at least has significant behavioral consequences.
once, so that a portion of the receptor lies outside the cell There is great interest in developing drugs that differentiate
and another portion lies inside. Dopamine receptors all belong between D1 and D5 receptors or among the D2-like receptors,
to the superfamily of proteins called seven-transmembrane both as research tools and because of the possibility that
receptors because they traverse the membrane 7 times, serpen- selective blockade or stimulation of only one subtype will be
tine receptors because of the manner in which they wind back a more effective treatment for a disease that is currently treated
and forth across the membrane, or G protein-coupled recep- by blockade or stimulation of the D1-like or D2-like subfamily
tors because most of the effects of neurotransmitter binding (Table 1). It is still not possible to differentiate pharma-
to the receptors are mediated by activation of G proteins. cologically between D1 and D5 receptors, two subtypes with
The superfamily of seven-transmembrane receptors includes very similar sequence in the membrane-spanning helices
receptors for light, odors, and calcium, in addition to most (Figure 1(a)). On the other hand, the use of antagonists that
neurotransmitters. Although all dopamine receptors have are highly selective for only one of the three subtypes of the
seven membrane-spanning regions with four intracellular D2-like receptor subfamily, particularly for the D4 receptor,
domains (loops 1–3 and the carboxy terminus) and four extra- has demonstrated that dopamine binding to D3 or D4 recep-
cellular domains (the amino terminal extension and extracel- tors in rats has behavioral effects that are very different from
lular loops 1–3), the D1-like receptors have relatively short D2 receptor-stimulated locomotor activation. Mice that have
third intracellular loops and relatively long carboxy termini null mutations in the gene for one receptor subtype, and thus
compared to the D2-like receptors (Figure 1). do not express functional protein for that subtype, have also
As illustrated in Figure 1, the presence of specific amino acid been very useful both for evaluating the in vivo selectivity of
residues at certain locations across receptor subtypes, or amino putative subtype-selective drugs and for determining different
acid sequence homology, is highest within the membrane- behavioral effects mediated by each receptor subtype.
spanning regions of seven-transmembrane receptors. This is
primarily because maintaining the three-dimensional structure
of a receptor so that it is relatively quiescent until activated Dopamine Receptor Signaling
by the binding of a neurotransmitter such as dopamine
requires precise packing of the membrane-spanning alpha- Most of the effects of dopamine receptors on cellular func-
helices and a network of interhelical bonds that constrain the tion are mediated by activation of heterotrimeric GTP-bind-
movement of the helices. Random mutations in these regions ing proteins called G proteins. Binding of dopamine to
would be often deleterious and selected against because of the amino acids within the membrane-spanning helices of a
relatively high likelihood of disrupting helix packing or inter- dopamine receptor disrupts the interhelical bonds that
helical bonds. Within a family of receptors for one neurotrans- hold the receptor in an inactive state. The resulting move-
mitter or for several structurally related neurotransmitters, such ment of one or more of the helices exposes amino acids on
as the catecholamines dopamine and norepinephrine, sequence the cytoplasmic face of the membrane that bind to and
homology also reflects the conservation of amino acids that bind activate G proteins. D1-like and D2-like receptors have
the neurotransmitter; for small molecule neurotransmitters such very different signaling properties as a result of differential
as dopamine, these amino acids are typically in the membrane- selection of G protein subtypes.
spanning helices, which form a water-accessible binding pocket
within the membrane lipid bilayer.
G Protein Coupling
Although depicted as single receptors in Figure 1, the func-
tioning holoreceptor is probably at least a dimer of two dopa- Heterotrimeric G proteins are composed of a, b, and g
mine receptors. Higher-order oligomers, such as tetramers, are subunits, and are generally named according to the subtype
also likely to exist. Oligomers may be homomers composed of of Ga subunit. D1-like receptors that have been stimulated
two or more copies of the same subunit or heteromers incor- by dopamine or other D1-receptor agonists activate two
porating more than one receptor subtype. Some oligomers, G proteins that stimulate adenylate cyclase, Gas and the closely
such as the D1:D2 oligomer, have novel properties such as related G protein, Gaolf (Table 1). (The latter G protein was
unique pharmacological profiles and distinct mechanisms of first identified as mediating olfactory responses to receptors for
signaling. odorants.) D2-like receptors activate the Gai subtypes, named
after their ability to inhibit adenylate cyclase, and the closely
related G protein Gao. That these G proteins are substrates for
Dopamine Receptor Subtype-Selective Drugs adenosine diphosphate (ADP)-ribosylation by cholera toxin,
which persistently activates Gas, or pertussis toxin, which inac-
D1 and D2 receptor-selective drugs have been very useful for tivates Gai/o, has contributed importantly to determining their
differentiating between the behavioral and biochemical effects role in dopamine receptor signaling.
172 Signaling | Dopamine Receptors

Table 1 Features of human dopamine receptor subtypes

Type of feature Dopamine receptor subtype

D1 D5 D2 D3 D4

Length (amino 446 477 443a 400 387b

acids)
Introns in coding No No Yes Yes Yes
region
G protein Gas/Gaolf Gas Gai/o Gai/o Gai/o
coupling
Agonists SKF38393 SKF38393 Quinpirole Quinpirole Quinpirole
6-Cl-APB 6-Cl-APB 7-OH-DPAT 7-OH-DPAT 7-OH-DPAT
PD128907 PD168077
Antagonists SCH23390 SCH23390 L-741,626 GR 103691 L-741,7141
U99194 L-745,870
Radioligands [3H]SCH 23390 [3H]SCH [3H]spiperone [3H]spiperone [3H]spiperone
23390
[125I]SCH23982 [125I] [3H]YM-09151-2 [3H]YM-09151-2 [3H]YM-09151-2
SCH23982 [3H]7-OH-DPAT
Localizationc Caudate-putamen, cerebral Hippocampus, Caudate-putamen, substantia Nucleus Cerebral cortex,
cortex, substantia nigra, cerebral nigra, intermediate and anterior accumbens, hypothalamus,
parathyroid gland cortex pituitary gland olfactory olfactory bulb
tubercle
Splice variants None None D2L/D2S D3nfd None
Allelic variantse None Leu88!Phe Val96!Ala Ser9!Gly Gly11!Arg
Ala269!Val Pro310!Ser 12 bp repeat in
Pro330!Gln Ser311!Cys exon 1
Cys- 21 bp deletion in
335!stop exon 1
Asn351!Asp 13 bp deletion in
exon 1
Val194!Gly
Ser453!Cys 48 bp repeat in
exon 3
a
Length of D2L; D2S is 414 amino acids long.
b
Length of the variant with two repeats (D4.2) although actual length depends on the number of repeat units, which varies from 2 to 10.
c
Selected tissues and brain regions with relatively high expression of the subtype are listed.
d
D3nf is a frame-shifted variant with D3 receptor sequence only through the fifth membrane-spanning helix. Although shorter-truncated splice variants of D3 mRNA also exist, D3nf is
the only one for which expression of the protein has been demonstrated.
e
Only variants that alter the protein sequence are listed.

Signaling Pathways combinations, for reasons that have not been determined,
activation of other types of G proteins such as Gas does not
As suggested by their activation of G proteins that stimulate
produce the same Gbg-mediated signaling that is observed
adenylate cyclase, most effects of D1-like receptor stimulation
after receptor-mediated activation of Gai/o. D2 receptors also
are mediated by increased levels of cyclic AMP and cyclic AMP-
signal via a pathway that requires the scaffolding protein
dependent protein phosphorylation. D1 receptor-stimulated
arrestin3, which recruits the protein kinase Akt and protein
protein phosphorylation alters the activity of other protein
phosphatase 2A, leading to the dephosphorylation and inhibi-
kinases, receptors, protein phosphatases, ion channels, and
tion of Akt.
transcription factors. Under some conditions, D1-like recep-
tors also activate Gaq, leading to calcium mobilization. D2-like
receptors inhibit the activity of adenylate cyclase via Gai. Distribution of Dopamine Receptors
D2-like receptors also modulate many other signaling path-
ways, most of them as a result of the liberation of G-protein The D1 and D2 dopamine receptors are overall the most abun-
bg subunits that occurs when seven-transmembrane receptors dant dopamine receptor subtypes. The D1 receptor is expressed
activate Gai/o proteins. Gbg-regulated pathways that are regu- most highly in the brain, with lower expression in peripheral
lated by stimulation of D2-like receptors include several forms tissues such as the parathyroid gland, renal, mesenteric, and
of adenylate cyclase, ion channels, phospholipase C, and coronary vascular beds, and the kidney. Within the brain, the
mitogen-activated protein (MAP) kinases. Although the basic D1 receptor is most abundant in the caudate-putamen and
mechanism of activation of heterotrimeric G proteins by other basal forebrain nuclei such as the nucleus accumbens,
receptors is probably the same for all receptor–G protein and is also found in the cerebral cortex and the substantia nigra
 Signaling | Dopamine Receptors 173

pars reticulata. The D5 receptor is expressed at much lower the treatment of schizophrenia and other psychoses. D2-like
levels in the same basal forebrain nuclei, the cerebral cortex, receptor antagonists are also used for the treatment of nausea
and hippocampus. The D2 receptor is expressed most highly in and vomiting, for delirium or dementia of unknown cause,
the intermediate pituitary gland, with abundant expression and for the symptomatic treatment of hyperactive movement
also observed in the anterior pituitary and in a number of disorder such as Tourette’s syndrome and Huntington’s dis-
brain regions including the caudate-putamen and other nuclei ease. Dopamine-receptor agonists alleviate the symptoms of
of the basal ganglia, the substantia nigra pars compacta, and the Parkinson’s disease and are often used in combination with
cerebral cortex. The D4 receptor is expressed in most of the the dopamine precursor dihydroxyphenylalanine (L-DOPA).
same forebrain regions as the D2 receptor and in the cerebral The D2-like receptor agonist, bromocriptine, is used to
cortex, albeit at a lower level. Whereas the D2 receptor is most treat hyperprolactinemia because of the inhibitory effect of
abundant in dorsal areas of the striatum, the D3 receptor is also anterior pituitary D2 receptors on prolactin secretion. When
expressed in the basal forebrain but is more abundant in the hyperprolactinemia results from a prolactin-secreting tumor,
ventral nuclei (nucleus accumbens and olfactory tubercle). treatment with bromocriptine also decreases the size of the
tumor. Dopamine or D1 agonists such as fenoldopam cause
D1 receptor-mediated vasodilation, thus increasing glomerular
Dopamine Receptor Variants filtration, renal blood flow, and sodium excretion, and are
used to manage types of shock associated with low cardiac
Although there are only five mammalian dopamine receptor output and compromised renal function.
genes that give rise to D1–5 receptors, four of the genes pro-
duce multiple receptor variants (Table 1). For example, the D2
receptor has two variants that result from alternative splicing of
See also: Signaling: Gs Family of Heterotrimeric G Proteins.
the RNA that is transcribed from the DRD2 gene. The long
form of the D2 receptor, D2L, contains a 29-amino-acid insert
encoded by an exon that is spliced out of the short form, D2S.
Recent evidence suggests that D2S and D2L might serve very Further Reading
different functions as autoreceptors that regulate dopamine
release and as postsynaptic receptors that mediate the actions Bunzow JR, Van Tol HHM, Grandy DK, et al. (1988) Cloning and expression of a rat D2
of dopamine on nondopaminergic neurons, respectively. In dopamine receptor cDNA. Nature 336: 783–787.
Carlsson A, Lindqvist M, Magnusson T, and Waldeck B (1958) On the presence of
contrast to splice variants that are derived from a single gene 3-hydroxytyramine in brain. Science 127: 471.
sequence and that are present in everybody, there are also Emilien G, Maloteaux JM, Geurts M, Hoogenberg K, and Cragg S (1999) Dopamine
dopamine receptor variants transcribed from distinct gene receptors – physiological understanding to therapeutic intervention potential.
sequences, so that each individual expresses only one or two Pharmacology and Therapeutics 84: 133–156.
Jose PA, Eisner GM, and Felder RA (1998) Renal dopamine receptors in health and
of the two or more existing variants. For example, there are at
hypertension. Pharmacology and Therapeutics 80: 149–182.
least 27 allelic variants of the human D4 receptor that have Meador-Woodruff JA, Damask SP, Wang J, et al. (1996) Dopamine receptor mRNA
from 2 to 10 copies of an imperfectly repeated 48 nucleotide expression in human striatum and neocortex. Neuropsychopharmacology
(16-amino-acid) sequence in the third intracellular loop of the 15: 17–29.
receptor. There is considerable interest in the possibility that Neve KA (ed.) (2010) The Dopamine Receptors, 2nd edn. New York, NY: Humana
Press.
these allelic variants also vary in functional characteristics. Sealfon SC and Olanow CW (2000) Dopamine receptors: From structure to behavior.
Trends in Neurosciences 23: S34–S40.
Sidhu A, Laruelle M, and Vernier P (eds.) (2003) Dopamine Receptors and
Therapeutic Uses for Dopamine Receptor Transporters: Function, Imaging, and Clinical Implication. New York, NY: Marcel
Agonists and Antagonists Dekker.
Vallone D, Picetti R, and Borrelli E (2000) Structure and function of dopamine receptors.
Neuroscience and Biobehavioral Reviews 24: 125–132.
By far, the most common therapeutic purpose for drugs that act
on dopamine receptors is the use of D2 receptor antagonists for