Dopamine receptor

thumb|class=skin-invert-image|[[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 signalling through different protein (dopamine receptor-interacting proteins) interactions. 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 signalling. Abnormal dopamine receptor signalling and dopaminergic nerve function is implicated in several neuropsychiatric disorders. Thus, dopamine receptors are common neurologic drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors.

Subtypes

The existence of multiple types of receptors for dopamine was first proposed in 1976. 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.

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. D_1-2 receptor subtypes are found at 10–100 times the levels of the D_3-5 subtypes.

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).

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

• D₂ is encoded by the Dopamine receptor D₂ 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).
• 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.
• D₄ is encoded by the Dopamine receptor D₄ gene (). The D₄ receptor gene displays polymorphisms that differ in a variable number tandem repeat present within the coding sequence of exon 3. 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.

Receptor heteromers

Dopamine receptors have been shown to heteromerize with a number of other G protein-coupled receptors. Especially the D2 receptor is considered a major hub within the GPCR heteromer network. Protomers consist of

Isoreceptors

• D₁–D₂
• D₁–D₃ <!--Marcellino et al., 2008-->
• D₂–D₃ <!--Scarselli et al., 2001-->
• D₂–D₄ <!--Borroto-Escuela et al., 2011b; Gonzàles et al., 2012-->
• D₂–D₅ <!--So et al., 2009-->

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

Signalling 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.

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.

Role in the central nervous system

Dopamine receptors control neural signalling that modulates many important behaviours, such as spatial working memory. Dopamine also plays an important role in the reward system, incentive salience, cognition, prolactin release, emesis, and motor function.

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. Such receptor subtypes have also been discovered in the epicardium, myocardium, and endocardium of the heart. In rats, D₁-like receptors are present on the smooth muscle of the blood vessels in most major organs.

D₄ receptors have been identified in the atria of rat and human hearts. Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signalling through dopamine receptors. 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.

Recent studies have found that beta cells, as well as other endocrine and exocrine pancreatic cells, express D2 receptors and that beta cells co-secrete dopamine along with insulin. Dopamine has been purported to be a negative regulator of insulin, 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. Traditional/typical antipsychotic medications function by altering the dopamine pathway in the brain, such as blocking D2 receptors. Common side effects of these medications include rapid weight gain and glycemic dysregulation, among others. 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.

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. 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

In disease

Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including social phobia, Tourette's syndrome, Parkinson's disease, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug and alcohol dependence. 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.

Addictive drugs

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. 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 signalling. When this occurs, particularly in the nucleus accumbens, increased D₁ and decreased D₂ The role between dopamine and pathological gambling may be a link between cerebrospinal fluid measures of dopamine and dopamine metabolites in pathological gambling. 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. This can occur in animal models and humans with defective dopamine receptor activity, particularly D₁. 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.

Dopamine regulation

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.

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). 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. According to one study, 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. A recent news article 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&nbsp;days. Cocaine upregulates D₃ receptors in the nucleus accumbens, further reinforcing drug seeking behaviour. and Caffeine increases striatal dopamine D₂/D₃ receptor availability in the human brain, Caffeine, or other more selective adenosine A2A receptor antagonists, causes significantly less motor stimulation in dopamine D₂ receptor.

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. Relatively high doses of dopaminergic stimulants will result in cognitive deficits. tags and the tag below -->

External links

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