Dopamine receptor

File:Dopamin - Dopamine.svg

Dopamine

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein (dopamine receptor-interacting proteins) interactions.<ref>Template:Cite journal</ref> The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

Dopamine receptors are implicated in many neurological processes, including motivational and incentive salience, cognition, memory, learning, and fine motor control, as well as modulation of neuroendocrine signaling. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders.<ref name="Girault, 2004">Template:Cite journal</ref> Thus, dopamine receptors are common neurologic drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors.

Subtypes

Template:More citations needed The existence of multiple types of receptors for dopamine was first proposed in 1976.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> There are at least five subtypes of dopamine receptors, D₁, D₂, D₃, D₄, and D₅. The D₁ and D₅ receptors are members of the D₁-like family of dopamine receptors, whereas the D₂, D₃ and D₄ receptors are members of the D₂-like family. There is also some evidence that suggests the existence of possible D₆ and D₇ dopamine receptors, but such receptors have not been conclusively identified.<ref name="Contreras, 2002">Template:Cite journal</ref>

At a global level, D₁ receptors have widespread expression throughout the brain. The relative amount of DA receptors is in the following order: D1 > D2 > D3 > D5 > D4.<ref>Template:Cite journal</ref> D_1-2 receptor subtypes are found at 10–100 times the levels of the D_3-5 subtypes.<ref name="Hurley, 2006">Template:Cite journal</ref>

D₁-like family

The D₁-like family receptors are coupled to the G protein G_sα. D₁ is also coupled to G_olf.

G_sα subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP).<ref name="Dopamine receptor signaling">Template:Cite journal</ref>

• D₁ is encoded by the Dopamine receptor D₁ gene (Template:Gene).
• D₅ is encoded by the Dopamine receptor D₅ gene (Template:Gene).

D₂-like family

The D₂-like family receptors are coupled to the G protein G_iα, which directly inhibits the formation of cAMP by inhibiting the enzyme adenylyl cyclase.<ref name="Neves_2002_Gprotein">Template:Cite journal</ref>

• D₂ is encoded by the Dopamine receptor D₂ gene (Template:Gene), of which there are two forms: D₂Sh (short) and D₂Lh (long):
  • The D₂Sh form is pre-synaptically situated, having modulatory functions (viz., autoreceptors, which regulate neurotransmission via feedback mechanisms. It affects synthesis, storage, and release of dopamine into the synaptic cleft).<ref name=D2sh>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• • The D₂Lh form may function as a classical post-synaptic receptor, i.e., transmit information (in either an excitatory or an inhibitory fashion) unless blocked by a receptor antagonist or a synthetic partial agonist.<ref name=D2sh/>
• D₃ is encoded by the Dopamine receptor D₃ gene (Template:Gene). Maximum expression of dopamine D₃ receptors is noted in the islands of Calleja and nucleus accumbens.<ref name="Suzuki_1998_D3">Template:Cite journal</ref>
• D₄ is encoded by the Dopamine receptor D₄ gene (Template:Gene). The D₄ receptor gene displays polymorphisms that differ in a variable number tandem repeat present within the coding sequence of exon 3.<ref>NCBI Database</ref> Some of these alleles are associated with greater incidence of certain disorders. For example, the D_4.7 alleles have an established association with attention-deficit hyperactivity disorder.<ref name="pmid12192625">Template:Cite journal</ref><ref name="pmid14702261">Template:Cite journal</ref><ref name="pmid14699430">Template:Cite journal</ref>

Receptor heteromers

Dopamine receptors have been shown to heteromerize with a number of other G protein-coupled receptors.<ref name="DA receptor heterodimers">Template:Cite journal</ref> Especially the D2 receptor is considered a major hub within the GPCR heteromer network.<ref name="pmid24830558">Template:Cite journal</ref> Protomers consist of

Isoreceptors<ref name="pmid26418645">Template:Cite journal</ref>

• D₁–D₂
• D₁–D₃
• D₂–D₃
• D₂–D₄
• D₂–D₅

Non-isoreceptors

• D₁–adenosine A₁
• D₂–adenosine A_2A
• D₂–ghrelin receptor
• D_2sh–TAAR1 (an autoreceptor heteromer)
• D₄–adrenoceptor α_1B
• D₄–adrenoceptor β₁

Signaling mechanism

Dopamine receptor D₁ and Dopamine receptor D₅ are G_s coupled receptors that stimulate adenylyl cyclase to produce cAMP, which in turn increases intracellular calcium and mediates a number of other functions. The D2 class of receptors produce the opposite effect, as they are G_αi and/or G_αo coupled receptors, which blocks the activity of adenylyl cyclase. cAMP mediated protein kinase A activity also results in the phosphorylation of DARPP-32, an inhibitor of protein phosphatase 1. Sustained D1 receptor activity is kept in check by Cyclin-dependent kinase 5. Dopamine receptor activation of Ca²⁺/calmodulin-dependent protein kinase II can be cAMP dependent or independent.<ref name="receptor mechanism">Template:Cite journal</ref>

The cAMP mediated pathway results in amplification of PKA phosphorylation activity, which is normally kept in equilibrium by PP1. The DARPP-32 mediated PP1 inhibition amplifies PKA phosphorylation of AMPA, NMDA, and inward rectifying potassium channels, increasing AMPA and NMDA currents while decreasing potassium conductance.<ref name="Dopamine receptor signaling"/>

cAMP independent

D1 receptor agonism and D2 receptor blockade also increases mRNA translation by phosphorylating ribosomal protein s6, resulting in activation of mTOR. The behavioral implications are unknown. Dopamine receptors may also regulate ion channels and BDNF independent of cAMP, possibly through direct interactions. There is evidence that D1 receptor agonism regulates phospholipase C independent of cAMP, however implications and mechanisms remain poorly understood. D2 receptor signaling may mediate protein kinase B, arrestin beta 2, and GSK-3 activity, and inhibition of these proteins results in stunting of the hyperlocomotion in amphetamine treated rats. Dopamine receptors can also transactivate Receptor tyrosine kinases.<ref name="receptor mechanism"/>

Beta Arrestin recruitment is mediated by G-protein kinases that phosphorylate and inactivate dopamine receptors after stimulation. While beta arrestin plays a role in receptor desensitization, it may also be critical in mediating downstream effects of dopamine receptors. Beta arrestin has been shown to form complexes with MAP kinase, leading to activation of extracellular signal-regulated kinases. Furthermore, this pathway has been demonstrated to be involved in the locomotor response mediated by dopamine receptor D1. Dopamine receptor D2 stimulation results in the formation of an Akt/Beta-arrestin/PP2A protein complex that inhibits Akt through PP2A phosphorylation, therefore disinhibiting GSK-3.<ref>Template:Cite journal</ref>

Role in the central nervous system

Template:Further Template:Further Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory.<ref name="Williams, 2006">Template:Cite journal</ref> Dopamine also plays an important role in the reward system, incentive salience, cognition, prolactin release, emesis and motor function.<ref>Template:Cite book</ref>

Non-CNS dopamine receptors

Cardio-pulmonary system

In humans, the pulmonary artery expresses D₁, D₂, D₄, and D₅ and receptor subtypes, which may account for vasodilatory effects of dopamine in the blood.<ref name="Ricci, 2006">Template:Cite journal</ref> Such receptor subtypes have also been discovered in the epicardium, myocardium, and endocardium of the heart.<ref name="Cavallotti, 2010">Template:Cite journal</ref> In rats, D₁-like receptors are present on the smooth muscle of the blood vessels in most major organs.<ref name="Hussain, 2003">Template:Cite journal</ref>

D₄ receptors have been identified in the atria of rat and human hearts.<ref name="Ricci, 1998">Template:Cite journal</ref> Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.<ref name="Contreras, 2002"/>

Renal system

Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density.<ref name="Hussain, 2003"/> In rats, D₁-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D₂-like receptors are present on the glomeruli, zona glomerulosa cells of the adrenal cortex, renal tubules, and postganglionic sympathetic nerve terminals.<ref name="Hussain, 2003"/> Dopamine signaling affects diuresis and natriuresis.<ref name="Contreras, 2002"/>

The Pancreas

The role of the pancreas<ref>Template:Citation</ref> is to secrete digestive enzymes via exocrine glands and hormones via endocrine glands. Pancreatic endocrine glands, composed of dense clusters of cells called the Islets of Langerhans, secrete insulin, glucagon, and other hormones essential for metabolism and glycemic control. Insulin secreting beta cells have been intensely researched due to their role in diabetes.<ref>Template:Cite journal</ref>

Recent studies have found that beta cells, as well as other endocrine and exocrine pancreatic cells, express D2 receptors<ref>Template:Cite journal</ref> and that beta cells co-secrete dopamine along with insulin.<ref>Template:Cite journal</ref> Dopamine has been purported to be a negative regulator of insulin,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> meaning that bound D2 receptors inhibit insulin secretion. The connection between dopamine and beta cells was discovered, in part, due to the metabolic side-effects of certain antipsychotic medications.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Traditional/typical antipsychotic medications function by altering the dopamine pathway in the brain, such as blocking D2 receptors.<ref>Template:Cite journal</ref> Common side effects of these medications include rapid weight gain and glycemic dysregulation, among others.<ref>Template:Cite journal</ref> The effects of these medications are not limited to the brain, so off-target effects in other organs such as the pancreas have been proposed as a possible mechanism.<ref>Template:Cite journal</ref>

Adipose Tissue

Dopamine receptors D1, D2, D4, and D5 are present in human subcutaneous, visceral, and brown adipose tissue, and have been implicated in lipid and glucose metabolism, and thermogenesis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Dopamine that reaches dopamine receptors in adipose tissue can originate from multiple sources: from the circulation, sympathetic nerves innervating adipose tissue that release dopamine from nerve terminals, local synthesis, or immune cells<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

In disease

Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including social phobia,<ref name = "pmid10698826">Template:Cite journal</ref> Tourette's syndrome,<ref name="Kienast, 2006">Template:Cite journal</ref> Parkinson's disease,<ref name="Fuxe, 2006">Template:Cite book</ref> schizophrenia,<ref name="Kienast, 2006"/> neuroleptic malignant syndrome,<ref name="pmid12555236">Template:Cite journal</ref> attention-deficit hyperactivity disorder (ADHD),<ref name="Faraone, 2006">Template:Cite journal</ref> and drug and alcohol dependence.<ref name="Kienast, 2006"/><ref name="Hummel, 2002"/>

Attention-deficit hyperactivity disorder

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Dopamine receptors have been recognized as important components in the mechanism of ADHD for many years. Drugs used to treat ADHD, including methylphenidate and amphetamine, have significant effects on neuronal dopamine signaling. Studies of gene association have implicated several genes within dopamine signaling pathways; in particular, the D_4.7 variant of D₄ has been consistently shown to be more frequent in ADHD patients.<ref name="Gornick, 2007">Template:Cite journal</ref> ADHD patients with the 4.7 allele also tend to have better cognitive performance and long-term outcomes compared to ADHD patients without the 4.7 allele, suggesting that the allele is associated with a more benign form of ADHD.<ref name="Gornick, 2007"/>

The D_4.7 allele has suppressed gene expression compared to other variants.<ref name="Schoots, 2003">Template:Cite journal</ref>

Addictive drugs

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Dopamine is the primary neurotransmitter involved in the reward and reinforcement (mesolimbic) pathway in the brain. Although it was a long-held belief that dopamine was the cause of pleasurable sensations such as euphoria, many studies and experiments on the subject have demonstrated that this is not the case; rather, dopamine in the mesolimbic pathway is responsible for behaviour reinforcement ("wanting") without producing any "liking" sensation on its own.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="NIDA drugs and brain">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Mesolimbic dopamine and its related receptors are a primary mechanism through which drug-seeking behaviour develops (Incentive Salience), and many recreational drugs, such as cocaine and substituted amphetamines, inhibit the dopamine transporter (DAT), the protein responsible for removing dopamine from the neural synapse. When DAT activity is blocked, the synapse floods with dopamine and increases dopaminergic signaling. When this occurs, particularly in the nucleus accumbens,<ref name="Di Chiara, 2004">Template:Cite journal</ref> increased D₁<ref name="Hummel, 2002">Template:Cite journal</ref> and decreased D₂<ref name="Di Chiara, 2004" /> receptor signaling mediates the "incentive salience" factor and can significantly increase positive associations with the drug in the brain.<ref name="NIDA drugs and brain" />

Pathological gambling

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Pathological gambling is classified as a mental health disorder that has been linked to obsessive-compulsive spectrum disorder and behavioral addiction. Dopamine has been associated with reward and reinforcement in relation to behaviors and drug addiction.<ref name=":1">Template:Cite journal</ref> The role between dopamine and pathological gambling may be a link between cerebrospinal fluid measures of dopamine and dopamine metabolites in pathological gambling.<ref>Template:Cite journal</ref> Molecular genetic study shows that pathological gambling is associated with the TaqA1 allele of the Dopamine Receptor D2 (DRD2) dopamine receptor. Furthermore, TaqA1 allele is associated with other reward and reinforcement disorders, such as substance abuse and other psychiatric disorders. Reviews of these studies suggest that pathological gambling and dopamine are linked; however, the studies that succeed in controlling for race or ethnicity, and obtain DSM-IV diagnoses do not show a relationship between TaqA1 allelic frequencies and the diagnostic of pathological gambling.<ref name=":1" />

Schizophrenia

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} While there is evidence that the dopamine system is involved in schizophrenia, the theory that hyperactive dopaminergic signal transduction induces the disease is controversial. Psychostimulants, such as amphetamine and cocaine, indirectly increase dopamine signaling; large doses and prolonged use can induce symptoms that resemble schizophrenia. Additionally, many antipsychotic drugs target dopamine receptors, especially D₂ receptors.

Genetic hypertension

Dopamine receptor mutations can cause genetic hypertension in humans.<ref name="Jose, 2003">Template:Cite journal</ref> This can occur in animal models and humans with defective dopamine receptor activity, particularly D₁.<ref name="Hussain, 2003"/>

Parkinson's disease

Parkinson's disease is associated with the loss of cells responsible for dopamine synthesis and other neurodegenerative events.<ref name=":1" /> Parkinson's disease patients are treated with medications which help to replenish dopamine availability, allowing relatively normal brain function and neurotransmission.<ref>Template:Cite journal</ref> Research shows that Parkinson's disease is linked to the class of dopamine agonists instead of specific agents. Reviews touch upon the need to control and regulate dopamine doses for Parkinson's patients with a history of addiction, and those with variable tolerance or sensitivity to dopamine.<ref name=":0">Template:Cite journal</ref>

Dopamine regulation

Template:See also Dopamine receptors are typically stable, however sharp (and sometimes prolonged) increases or decreases in dopamine levels can downregulate (reduce the numbers of) or upregulate (increase the numbers of) dopamine receptors.<ref name="pmid15177784 ">Template:Cite journal</ref>

Haloperidol, and some other antipsychotics, have been shown to increase the binding capacity of the D₂ receptor when used over long periods of time (i.e. increasing the number of such receptors).<ref>Template:Cite journal</ref> Haloperidol increased the number of binding sites by 98% above baseline in the worst cases, and yielded significant dyskinesia side effects.

Addictive stimuli have variable effects on dopamine receptors, depending on the particular stimulus.<ref name="Natural and drug addictions">Template:Cite journalTable 1"</ref> According to one study,<ref>Template:Cite journal</ref> cocaine, opioids like heroin, amphetamine, alcohol, and nicotine cause decreases in D₂ receptor quantity. A similar association has been linked to food addiction, with a low availability of dopamine receptors present in people with greater food intake.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite journal</ref> A recent news article<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> summarized a U.S. DOE Brookhaven National Laboratory study showing that increasing dopamine receptors with genetic therapy temporarily decreased cocaine consumption by up to 75%. The treatment was effective for 6 days. Cocaine upregulates D₃ receptors in the nucleus accumbens, further reinforcing drug seeking behavior.<ref>Template:Cite journal</ref> and Caffeine increases striatal dopamine D₂/D₃ receptor availability in the human brain,<ref>Template:Cite journal</ref> Caffeine, or other more selective adenosine A2A receptor antagonists, causes significantly less motor stimulation in dopamine D₂ receptor.<ref>Template:Cite journal</ref>

Certain stimulants will enhance cognition in the general population (e.g., direct or indirect mesocortical DRD1 agonists as a class), but only when used at low (therapeutic) concentrations.<ref name="Cognitive and motivational effects">Template:Cite journal</ref><ref name="Malenka_2009" /><ref name="Continuum">Template:Cite journal</ref> Relatively high doses of dopaminergic stimulants will result in cognitive deficits.<ref name="Malenka_2009">Template:Cite book</ref><ref name="Continuum" /> Template:FOSB addiction table

See also

• D2 short (presynaptic)
• Category:Dopamine agonists
• Category:Dopamine antagonists

External links

• {{#invoke:citation/CS1|citation

|CitationClass=web }}

• Zimmerberg, B., "Dopamine receptors: A representative family of metabotropic receptors, Multimedia Neuroscience Education Project (2002)
• Scholarpedia article on Dopamine anatomy