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==Human Dopamine D3 Receptor==
<Structure load='3PBL' size='500' frame='true' align='right' caption='Structure of the human dopamine D3 receptor in complex with eticlopride' scene='Insert optional scene name here' />
<Structure load='3PBL' size='500' frame='true' align='right' caption='Structure of the human dopamine D3 receptor in complex with eticlopride' scene='Insert optional scene name here' />
==Introduction==
==Introduction==
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are important in the central nervous system. Dopamine receptors are involved many neurological processes that comprise motivation, pleasure, cognition, memory, learning, and fine motor skills. There are five subtype dopamine receptors, D1, D2, D3, D4, and D5. The D3 receptor is a part of the D2-like family.<ref>Girault J, Greengard P (2004). "The neurobiology of dopamine signaling". Arch Neurol 61 (5): 641–4. doi:10.1001/archneur.61.5.641. PMID 15148138.</ref>  
Dopamine receptors are a class of metabotropic G protein-coupled receptors that are important in the central nervous system. Dopamine receptors are involved in many neurological processes that comprise motivation, pleasure, cognition, memory, learning, and fine motor skills. There are five subtype dopamine receptors, D1, D2, D3, D4, and D5. The D3 receptor is a part of the D2-like family.<ref>PMID:15148138</ref>  
 
==Function==
==Function==
Human dopamine D3 receptor is a protein that encoded by the dopamine receptor gene (DRD3).<ref>Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, Schwartz JC, Berger R (Oct 1991). "Chromosomal localization of the human D3 dopamine receptor gene". Hum Genet 87 (5): 618–20.</ref> The DRD3 gene codes for the D3 dopamine receptor that inhibits adenylyl cyclase through inhibitory G-proteins. This receptor is located in the brain, suggesting that the D3 receptor plays a role in cognitive and emotional functions.<ref>National Center for Biotechnology Information, U.S. National Library of Medicine. DRD3 dopamine receptor D3 [Homo sapiens]. 19 November 2011.</ref> The human dopamine D3 receptor is membrane-bound and scattered in the cytoplasm. Receptor stimulation causes internalization of the receptors at the perinuclear areas. This is followed by the spreading of the receptors to the membrane. DRD3 is contained in lipid rafts of renal proximal tubule cells.<ref>"G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor."
Human dopamine D3 receptor is a protein that is encoded by the dopamine receptor gene (DRD3).<ref>PMID: 1916765</ref> The DRD3 gene codes for the D3 dopamine receptor that inhibits adenylyl cyclase through inhibitory G-proteins. G-protein coupled receptors are a family of transmembrane proteins that transmit chemical signals from outside the cell to cause changes inside of the cell. Adenylate cyclase is part of the G-protein receptor's signaling and catalyze the conversion of ATP to cyclic AMP (cAMP).<ref>Reece, Jane; Campbell, Neil (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5.</ref> The D3 receptor is located in the brain, suggesting that it plays a role in cognitive and emotional functions.<ref>National Center for Biotechnology Information, U.S. National Library of Medicine. DRD3 dopamine receptor D3 [Homo sapiens]. 19 November 2011.</ref> The human dopamine D3 receptor is membrane-bound and scattered in the cytoplasm. Receptor stimulation causes internalization of the receptors at the perinuclear areas. This is followed by the spreading of the receptors to the membrane. DRD3 is also contained in lipid rafts of renal proximal tubule cells.<ref>PMID: 19520868</ref>
Villar V.A.M., Jones J.E., Armando I., Palmes-Saloma C., Yu P., Pascua A.M., Keever L., Arnaldo F.B., Wang Z., Luo Y., Felder R.A., Jose P.A.
 
J. Biol. Chem. 284:21425-21434(2009) [PubMed: 19520868] [Abstract]</ref>
==Structure==
==Structure==
Human dopamine D3 receptor is 64% helical and 1% beta sheet. The protein is composed of 20 helices and 3 beta sheet strands. The helices are made up of 312 residues and the bate sheets are made up of 9 residues. The entire protein consists of 481 residues.<ref>http://www.pdb.org/pdb/explore.do?structureId=3PBL</ref>
Human dopamine D3 receptor is 64% helical and 1% beta sheet. The protein is composed of 20 helices and 3 beta sheet strands. The helices are made up of 312 residues, and the beta sheets are made up of 9 residues. The entire protein consists of 481 residues.<ref name="structure">PMID: 21097933</ref> Dopamine D3 receptors are greatly expressed in the Islands of Calleja, a group of neural granule cells located within the ventral striatum in the brains of most animals, which is part of the limbic system. It is also found in the nucleus accumbens, a collection of neurons, and forms the main part of the ventral striatum.<ref>PMID:9473588</ref>
 
==Ligands==
==Ligands==
Many non-selective prescription drugs bind to the D3 receptor. Some agonist, agents that stimulate, dopamine receptors include<ref>http://en.wikipedia.org/wiki/Category:Dopamine_agonists</ref>:
Many non-selective prescription drugs bind to the D3 receptor. The binding of drugs either increases or inhibits the production of dopamine D3 receptors, which helps to diminish complications that are caused by certain diseases. Some agonists, agents that stimulate dopamine receptors, include:
*Amphetamine
*Amphetamine<ref>Jones S, Kornblum JL, Kauer JA (August 2000). "Amphetamine blocks long-term synaptic depression in the ventral tegmental area". J. Neurosci. 20 (15): 5575–80. PMID 10908593. http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=10908593.</ref>
*Dopaminergic
*Methamphetamine<ref>Cruickshank, CC.; Dyer, KR. (Jul 2009). "A review of the clinical pharmacology of methamphetamine.". Addiction 104 (7): 1085–99. doi:10.1111/j.1360-0443.2009.02564.x. PMID 19426289.</ref>
*Methamphetamine
Some antagonists, agents that inhibit dopamine receptors, include:
Some antagonists, agents that inhibit dopamine receptors include<ref>http://en.wikipedia.org/wiki/Category:Dopamine_antagonists</ref>:
*Clebopride<ref>Cuena Boy R, Maciá Martínez MA (1998). "[Extrapyramidal toxicity caused by metoclopramide and clebopride: study of voluntary notifications of adverse effects to the Spanish Drug Surveillance System]" (in Spanish). Atencion Primaria 21 (5): 289–95. PMID 9608114. Free full text</ref>
*Bromopride
*Nafadotride<ref>Pilla M, Perachon S, Sautel F, Garrido F, Mann A, Wermuth CG, Schwartz JC, Everitt BJ, Sokoloff P. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 agonist. Nature. 1999;400:371–375.</ref>
*Clebopride
Two ligands that are associated with the dopamine D3 receptor are 3-chloro-5-ethyl-N{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-6-hydroxyl-2-methyloxybenzamide (<scene name='Sandbox_Reserved_383/Etq/1'>ETQ</scene>) and maltose (<scene name='Sandbox_Reserved_383/Mal/1'>MAL</scene>).  ETQ binds to dopamine D3 receptor by Asp 110A and Phe346A. MAL binds by Asp 1020A, Glu 1022A, Glu1011A, and Leu1032A.<ref name="structure" />
*Eticlopride
*Nafadotride
Two ligands that are associated with dopamine D3 receptor are 3-chloro-5-ethyl-N{[(2S)-1-ethylpyrrolidin-2-yl]methyl}-6-hydroxyl-2-methyloxybenzamide (<scene name='Sandbox_Reserved_383/Etq/1'>ETQ</scene>) and maltose (<scene name='Sandbox_Reserved_383/Mal/1'>MAL</scene>).  ETQ binds to dopamine D3 receptor by Asp 110A and Phe346A. MAL binds by Asp 1020A, Glu 1022A, Glu1011A, and Leu1032A.<refhttp://www.pdb.org/pdb/explore.do?structureId=3PBL/>


==Diseases==
==Diseases==
Variations in the DRD3 gene is connected with essential tremor hereditary type 1 (ETM1). ETM1 is the most common movement disorder involving postural tremor of the arms, head, legs, body core, voice, jaw, and other facial muscles. This condition can be provoked by emotions, hunger, fatigue, and temperature extremes.<ref>"Linkage with the Ser9Gly DRD3 polymorphism in essential tremor families."
Variations in the DRD3 gene is connected with essential tremor hereditary type 1 (ETM1).<ref name="disease">PMID: 16650084</ref>
Lucotte G., Lagarde J.-P., Funalot B., Sokoloff P.
ETM1 is the most common movement disorder involving postural tremor of the arms, head, legs, body core, voice, jaw, and other facial muscles.
Clin. Genet. 69:437-440(2006) [PubMed: 16650084] [Abstract]</ref><ref>"A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor."
This condition can be provoked by emotions, hunger, fatigue, and temperature extremes.<ref name="disease" />
Jeanneteau F., Funalot B., Jankovic J., Deng H., Lagarde J.-P., Lucotte G., Sokoloff P.
 
Proc. Natl. Acad. Sci. U.S.A. 103:10753-10758(2006) [PubMed: 16809426] [Abstract]</ref> Disorders that are linked to variations in the DRD3 gene include social phobia<ref>Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M (2000). "Low dopamine D(2) receptor binding potential in social phobia". Am J Psychiatry 157 (3): 457–459. doi:10.1176/appi.ajp.157.3.457. PMID 10698826.</ref>, Tourette’s syndrome<ref>11Kienast T, Heinz A (2006). "Dopamine and the diseased brain". CNS Neurol Disord Drug Targets 5 (1): 109–31. doi:10.2174/187152706784111560. PMID 16613557.</ref>, Parkinson’s disease<ref>Fuxe K, Manger P, Genedani S, Agnati L (2006). The nigrostriatal DA pathway and Parkinson’s disease. "The nigrostriatal DA pathway and Parkinson's disease". J Neural Transm Suppl. Journal of Neural Transmission. Supplementa 70 (70): 71–83. doi:10.1007/978-3-211-45295-0_13. ISBN 978-3-211-28927-3. PMID 17017512.</ref>, schizophrenia<ref11Kienast T, Heinz A (2006). "Dopamine and the diseased brain". CNS Neurol Disord Drug Targets 5 (1): 109–31. doi:10.2174/187152706784111560. PMID 16613557./>, neuroleptic malignant syndrome<ref>13Mihara K, Kondo T, Suzuki A, et al. (2003). "Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome". Am. J. Med. Genet. B Neuropsychiatr. Genet. 117 (1): 57–60. doi:10.1002/ajmg.b.10025. PMID 12555236.</ref>, attention-deficit hyperactivinty disorder (ADHD)<ref>Faraone S, Khan S (2006). "Candidate gene studies of attention-deficit/hyperactivity disorder". J Clin Psychiatry 67 Suppl 8: 13–20. PMID 16961425.</ref>, and drug and alcohol dependence<ref11Kienast T, Heinz A (2006). "Dopamine and the diseased brain". CNS Neurol Disord Drug Targets 5 (1): 109–31. doi:10.2174/187152706784111560. PMID 16613557./><ref>Hummel M, Unterwald E (2002). "D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action". J Cell Physiol 191 (1): 17–27. doi:10.1002/jcp.10078. PMID 11920678</ref>.
==References==  
==References==
 
<Girault J, Greengard P (2004). "The neurobiology of dopamine signaling". Arch Neurol 61 (5): 641–4. doi:10.1001/archneur.61.5.641. PMID 15148138./>
<references />
<Le Coniat M, Sokoloff P, Hillion J, Martres MP, Giros B, Pilon C, Schwartz JC, Berger R (Oct 1991). "Chromosomal localization of the human D3 dopamine receptor gene". Hum Genet 87 (5): 618–20./>
<National Center for Biotechnology Information, U.S. National Library of Medicine. DRD3 dopamine receptor D3 [Homo sapiens]. 19 November 2011./>
<"G protein-coupled receptor kinase 4 (GRK4) regulates the phosphorylation and function of the dopamine D3 receptor."
Villar V.A.M., Jones J.E., Armando I., Palmes-Saloma C., Yu P., Pascua A.M., Keever L., Arnaldo F.B., Wang Z., Luo Y., Felder R.A., Jose P.A.
J. Biol. Chem. 284:21425-21434(2009) [PubMed: 19520868] [Abstract]/>
<http://www.pdb.org/pdb/explore.do?structureId=3PBL/>
<http://en.wikipedia.org/wiki/Category:Dopamine_agonists/>
<http://en.wikipedia.org/wiki/Category:Dopamine_antagonists/>
<"Linkage with the Ser9Gly DRD3 polymorphism in essential tremor families."
Lucotte G., Lagarde J.-P., Funalot B., Sokoloff P.
Clin. Genet. 69:437-440(2006) [PubMed: 16650084] [Abstract]/>
<"A functional variant of the dopamine D3 receptor is associated with risk and age-at-onset of essential tremor."
Jeanneteau F., Funalot B., Jankovic J., Deng H., Lagarde J.-P., Lucotte G., Sokoloff P.
Proc. Natl. Acad. Sci. U.S.A. 103:10753-10758(2006) [PubMed: 16809426] [Abstract]/>
<Schneier FR, Liebowitz MR, Abi-Dargham A, Zea-Ponce Y, Lin SH, Laruelle M (2000). "Low dopamine D(2) receptor binding potential in social phobia". Am J Psychiatry 157 (3): 457–459. doi:10.1176/appi.ajp.157.3.457. PMID 10698826./>
<Kienast T, Heinz A (2006). "Dopamine and the diseased brain". CNS Neurol Disord Drug Targets 5 (1): 109–31. doi:10.2174/187152706784111560. PMID 16613557./>
<Fuxe K, Manger P, Genedani S, Agnati L (2006). The nigrostriatal DA pathway and Parkinson’s disease. "The nigrostriatal DA pathway and Parkinson's disease". J Neural Transm Suppl. Journal of Neural Transmission. Supplementa 70 (70): 71–83. doi:10.1007/978-3-211-45295-0_13. ISBN 978-3-211-28927-3. PMID 17017512./>
<Mihara K, Kondo T, Suzuki A, et al. (2003). "Relationship between functional dopamine D2 and D3 receptors gene polymorphisms and neuroleptic malignant syndrome". Am. J. Med. Genet. B Neuropsychiatr. Genet. 117 (1): 57–60. doi:10.1002/ajmg.b.10025. PMID 12555236./>
Faraone S, Khan S (2006). "Candidate gene studies of attention-deficit/hyperactivity disorder". J Clin Psychiatry 67 Suppl 8: 13–20. PMID 16961425./>
Hummel M, Unterwald E (2002). "D1 dopamine receptor: a putative neurochemical and behavioral link to cocaine action". J Cell Physiol 191 (1): 17–27. doi:10.1002/jcp.10078. PMID 11920678/>
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