Dopamine receptor

Dopamine receptor 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. Furthermore, 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).

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.

Receptor heteromers

Dopamine receptors have been shown to heterodimerize with a number of other G protein-coupled receptors. The resulting dopamine receptor heterodimers include:

Signalling Mechanism

Dopamine receptor D1 and Dopamine receptor D5 are G_s coupled receptors that stimulate adenylyl cyclase to produce cAMP, increasing intracellular calcium among other cAMP mediated processes.. The D2 class of receptors produce the opposite effect, as they are G_αi coupled receptors, and block 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.

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.

Role of dopamine receptors in the central nervous system

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

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. 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 signaling through dopamine receptors.

Renal system

Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density. 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. Dopamine signaling affects diuresis and natriuresis.

Dopamine receptors 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, neuroleptic malignant syndrome, attention-deficit hyperactivity disorder (ADHD), and drug and alcohol dependence.

Attention-deficit hyperactivity disorder

Dopamine receptors have been recognized as important components in the etiology 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. 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.

The D_4.7 allele has suppressed gene expression compared to other variants.

Addictive drugs

Dopamine is the primary neurotransmitter involved in the reward pathway in the brain. Thus, drugs that increase dopamine signaling may produce euphoric effects. 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, increased D₁ and decreased D₂ receptor signaling mediates the "rewarding" stimulus of drug intake.

Schizophrenia

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. This can occur in animal models and humans with defective dopamine receptor activity, particularly D₁.

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, 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 days. Cocaine upregulates D₃ receptors in the nucleus accumbens, possibly contributing to drug seeking behavior.

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.