Dopamine receptor


Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system. Dopamine receptors activate different effectors through not only G-protein coupling, but also signalling through different protein 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. D1-2 receptor subtypes are found at 10–100 times the levels of the D3-5 subtypes.

D1-like family

The D1-like family receptors are coupled to the G protein Gsα. D1 is also coupled to Golf.
Gsα subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger cyclic adenosine monophosphate.
  • 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 Giα, 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 and D2Lh :
  • * The D2Sh form is pre-synaptically situated, having modulatory functions.
  • * The D2Lh form may function as a classical post-synaptic receptor, i.e., transmit information unless blocked by a receptor antagonist or a synthetic partial agonist.
  • D3 is encoded by the Dopamine receptor D3 gene. Maximum expression of dopamine D3 receptors is noted in the islands of Calleja and nucleus accumbens.
  • 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 D4.7 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
  • D2–D3
  • D2–D4
  • D2–D5
Non-isoreceptors
  • D1–adenosine A1
  • D2–adenosine A2A
  • D2–ghrelin receptor
  • D2sh–TAAR1
  • D4–adrenoceptor α1B
  • D4–adrenoceptor β1

    Signalling mechanism

and Dopamine receptor D5 are Gs 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 Gαi and/or Gαo 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.

cAMP independent

D1 receptor agonism and D2 receptor blockade also increases mRNA translation by phosphorylating ribosomal protein s6, resulting in activation of mTOR. The behavioural 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 signalling 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.
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.

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.

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 signalling affects diuresis and natriuresis.

Pancreas

The role of the pancreas 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