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Contents

Human Dopamine D3 Receptor

Structure of the human dopamine D3 receptor in complex with eticlopride

Drag the structure with the mouse to rotate

Introduction

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.[1]

Function

Human dopamine D3 receptor is a protein that is encoded by the dopamine receptor gene (DRD3).[2] The DRD3 gene codes for the D3 dopamine receptor that inhibits adenylyl cyclase through inhibitory G-proteins. G-proteins are a family of transmembrane proteins that transmit chemical signals outside the cell to cause changes inside of the cell. Adenylate cyclase is part of the G-proteins signalling and catalyze the conversion of ATP to cyclic AMP (cAMP).[3] This receptor is located in the brain, suggesting that the D3 receptor plays a role in cognitive and emotional functions.[4] 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.[5]

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.[6] 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.[7]

Image:250px-Islands of Calleja Rat.jpg
Islands of Calleja of rat brain stained in blue.
Image:250PX-~2.JPG
Nucleus accumbens visible in red.

Ligands

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 agonist, agents that stimulate, dopamine receptors include[8]:

  • Amphetamine
  • Dopaminergic
  • Methamphetamine

Some antagonists, agents that inhibit dopamine receptors include[9]:

  • Bromopride
  • Clebopride
  • 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 () and maltose (). ETQ binds to dopamine D3 receptor by Asp 110A and Phe346A. MAL binds by Asp 1020A, Glu 1022A, Glu1011A, and Leu1032A.[10]

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.[11][12] Disorders that are linked to variations in the DRD3 gene include social phobia[13], Tourette’s syndrome[14], Parkinson’s disease[15], schizophrenia[16], neuroleptic malignant syndrome[17], attention-deficit hyperactivinty disorder (ADHD)[18], and drug and alcohol dependence[19] [20].

References

  1. <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./>
  2. <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./>
  3. <Reece, Jane; Campbell, Neil (2002). Biology. San Francisco: Benjamin Cummings. ISBN 0-8053-6624-5./>
  4. <National Center for Biotechnology Information, U.S. National Library of Medicine. DRD3 dopamine receptor D3 [Homo sapiens]. 19 November 2011./>
  5. <"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]/>
  6. <http://www.pdb.org/pdb/explore.do?structureId=3PBL/>
  7. <Suzuki M, Hurd YL, Sokoloff P, Schwartz JC, Sedvall G (January 1998). "D3 dopamine receptor mRNA is widely expressed in the human brain". Brain Res. 779 (1–2): 58–74. doi:10.1016/S0006-8993(97)01078-0. PMID 9473588./>
  8. <http://en.wikipedia.org/wiki/Category:Dopamine_agonists/>
  9. <http://en.wikipedia.org/wiki/Category:Dopamine_antagonists/>
  10. <http://www.pdb.org/pdb/explore.do?structureId=3PBL/>
  11. <"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]/>
  12. <"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]/>
  13. <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./>
  14. <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./>
  15. <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./>
  16. <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./>
  17. <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./>
  18. <Faraone S, Khan S (2006). "Candidate gene studies of attention-deficit/hyperactivity disorder". J Clin Psychiatry 67 Suppl 8: 13–20. PMID 16961425./>
  19. <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./>
  20. <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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