Dopamine receptor
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Dopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
Dopamine receptors have key roles in many processes, including the control of motivation, learning, and fine motor movement, as well as modulation of neuroendocrine signaling. Abnormal dopamine receptor signaling and dopaminergic nerve function is implicated in several neuropsychiatric disorders.[1] Thus, dopamine receptors are common neurologic drug targets; antipsychotics are often dopamine receptor antagonists while psychostimulants are typically indirect agonists of dopamine receptors.
Contents |
[edit] Dopamine receptor subtypes
D1-like | D2-like | |||||
[citation needed] | ||||||
D1 | D5 | D2 | D3 | D4 | ||
---|---|---|---|---|---|---|
Apomorphine | + | + | + | + | + | |
Fenoldopam | + | + | + | ? | + | |
SKF 38393 | + | + | + | |||
SKF 82958 | + | + | ||||
Dihydrexidine | + | + | ||||
Quinpirole | + | + | ||||
Haloperidol | - | ? | - | - | ? | |
Flupentixol | - | ? | - | ? | ? | |
Fluphenazine | - | ? | ? | ? | ? | |
SCH 23390 | - | - | ||||
Spiperone | ? | - | ? | ? | ||
Raclopride | - | - | - | |||
Clozapine | - | - | - | - | - |
There are five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. 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.[2]
[edit] D1-like family
Activation of the D1-like family receptors is coupled to the G protein Gαs, which subsequently activates adenylyl cyclase, increasing the intracellular concentration of the second messenger Cyclic adenosine monophosphate (cAMP). Increased cAMP in neurons is typically excitatory and can induce an action potential by modulating the activity of ion channels.
[edit] D1
- D1 ("DRD1", Mendelian Inheritance in Man (OMIM) 126449)
[edit] D5
- D5 ("DRD5", Mendelian Inheritance in Man (OMIM) 126453)
[edit] D2-like family
D2-like activation is coupled to the G protein Gαi, which subsequently increased phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.
[edit] D2
- D2 ("DRD2", Mendelian Inheritance in Man (OMIM) 126450). There is a short version of D2 (D2Sh) and a long version of D2 (D2Lh):
- The D2Sh are pre-synaptic situated, having modulatory functions (called autoreceptor, they regulate the neurotransmission by feed-back mechanisms, i.e., synthesis, storage and release of dopamine into the synaptic cleft).
- The D2Lh may have the classic function of a post-synaptic receptor, i.e., keep going on the neurotransmission (excitatory or inhibitory) once blocked by a receptor antagonist or stimulated by the endogenous neurotransmitter itself or a synthetic full or partial agonist.
[edit] D3
- D3 ("DRD3", Mendelian Inheritance in Man (OMIM) 126451)
[edit] D4
- D4 ("DRD4", Mendelian Inheritance in Man (OMIM) 126452). D4 has the following variants D4.2, D4.3a, D4.3b, D4.4a, D4.4b, D4.4c, D4.4d, D4.4e, D4.5a, D4.5b, D4.6a, D4.6b, D4.7a, D4.7b, D4.7c, D4.7d, D4.8, D4.10. These variants differ in a variable number tandem repeat domain present within the coding sequence of exon 3. Some of these alleles are associated with greater incidence of certain diseases. For example, the D4.7 alleles have an established association with attention-deficit hyperactivity disorder.
[edit] Role of dopamine receptors in the central nervous system
Dopamine receptors control neural signaling that modulates many important behaviors, such as spatial working memory.[3]
[edit] Non-CNS dopamine receptors
[edit] Cardio-pulmonary system
In humans, the pulmonary artery expresses D1, D2, D4, and D5 and receptor subtypes, which may account for vasorelaxive effects of dopamine in the blood.[4] In rats, D1-like receptors are present on the smooth muscle of the blood vessels in most major organs.[5]
D4 receptors have been identified in the atria of rat and human hearts.[6] Dopamine increases myocardial contractility and cardiac output, without changing heart rate, by signaling through dopamine receptors.[2]
[edit] Renal system
Dopamine receptors are present along the nephron in the kidney, with proximal tubule epithelial cells showing the highest density.[5] In rats, D1-like receptors are present on the juxtaglomerular apparatus and on renal tubules, while D2-like receptors are present on the renal tubules, glomeruli, postganglionic sympathetic nerve terminals, and zona glomerulosa cells of the renal cortex.[5] Dopamine signaling affects diuresis and natriuresis.[2]
[edit] Dopamine receptors in disease
Dysfunction of dopaminergic neurotransmission in the CNS has been implicated in a variety of neuropsychiatric disorders, including Tourette's syndrome,[7] Parkinson's disease,[8] schizophrenia,[7] Attention-deficit hyperactivity disorder,[9] and drug and alcohol dependence.[7][10]
[edit] Drug abuse
Dopamine is the primary neurotransmitter involved in the reward pathways in the brain. Thus, drugs that increase dopmamine signaling may produce euphoric effects. Cocaine and methamphetamine—two examples of such drugs—alter the functionality of 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,[11] increased D1[10] and D2[11] receptor signaling mediates the "rewarding" stimulus of drug intake.[11]
[edit] Genetic hypertension
Dopamine receptor mutations can cause genetic hypertension in humans.[12] This can occur in animal models and humans with defective dopamine receptor activity, particularly D1.[5]
[edit] External links
- IUPHAR GPCR Database - Dopamine Receptors
- Zimmerberg, B., "Dopamine receptors: A representative family of metabotropic receptors, Multimedia Neuroscience Education Project (2002)
[edit] References
- ^ Girault J, Greengard P (2004). "The neurobiology of dopamine signaling". Arch Neurol 61 (5): 641-4. PMID 15148138.
- ^ a b c Contreras F, Fouillioux C, Bolívar A, Simonovis N, Hernández-Hernández R, Armas-Hernandez M, Velasco M (2002). "Dopamine, hypertension and obesity". J Hum Hypertens 16 Suppl 1: S13-7. PMID 11986886.
- ^ Williams G, Castner S (2006). "Under the curve: critical issues for elucidating D1 receptor function in working memory". Neuroscience 139 (1): 263-76. PMID 16310964.
- ^ Ricci A, Mignini F, Tomassoni D, Amenta F (2006). "Dopamine receptor subtypes in the human pulmonary arterial tree". Auton Autacoid Pharmacol 26 (4): 361-9. PMID 16968475.
- ^ a b c d Hussain T, Lokhandwala M (2003). "Renal dopamine receptors and hypertension". Exp Biol Med (Maywood) 228 (2): 134-42. PMID 12563019.
- ^ Ricci A, Bronzetti E, Fedele F, Ferrante F, Zaccheo D, Amenta F (1998). "Pharmacological characterization and autoradiographic localization of a putative dopamine D4 receptor in the heart". J Auton Pharmacol 18 (2): 115-21. PMID 9730266.
- ^ a b c Kienast T, Heinz A (2006). "Dopamine and the diseased brain". CNS Neurol Disord Drug Targets 5 (1): 109-31. PMID 16613557.
- ^ Fuxe K, Manger P, Genedani S, Agnati L (2006). "The nigrostriatal DA pathway and Parkinson's disease". J Neural Transm Suppl 70: 71-83. PMID 17017512.
- ^ Faraone S, Khan S (2006). "Candidate gene studies of attention-deficit/hyperactivity disorder". J Clin Psychiatry 67 Suppl 8: 13-20. PMID 16961425.
- ^ a b Hummel M, Unterwald E (2002). "D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action". J Cell Physiol 191 (1): 17-27. PMID 11920678.
- ^ a b c Di Chiara G, Bassareo V, Fenu S, De Luca M, Spina L, Cadoni C, Acquas E, Carboni E, Valentini V, Lecca D (2004). "Dopamine and drug addiction: the nucleus accumbens shell connection". Neuropharmacology 47 Suppl 1: 227-41. PMID 15464140.
- ^ Jose P, Eisner G, Felder R (2003). "Regulation of blood pressure by dopamine receptors". Nephron Physiol 95 (2): p19-27. PMID 14610323.
Adenosine - Adrenergic - Angiotensin - Bradykinin - Calcitonin - Cannabinoid - Chemokine - Cholecystokinin - Corticotropin-releasing hormone - C5A - Dopamine - Endothelin - FSH-receptor - GABA B - Galanin - Glucagon - Gonadotropin-releasing hormone - Histamine (H1, H2, H3, H4) - Luteinizing hormone/choriogonadotropin - Melanocortin (MC1R, MC2R) - Melatonin - Metabotropic glutamate - Muscarinic acetylcholine - Neurotensin - Olfactory - Opioid (Delta, Kappa, Mu, Sigma, Nociceptin) - Parathyroid hormone - Purinergics (P2Y) - Trace amine-associated - Secretin - Serotonin, all but 5-HT3 (5-HT2A)