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Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.
The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.
Levonantradol (CP 50,556-1) is a synthetic cannabinoid analog of dronabinol (Marinol) developed by Pfizer in the 1980s. It is around 30 times more potent than THC, and exhibits antiemetic and analgesic effects via activation of CB1 and CB2 cannabinoid receptors. Levonantradol is not currently used in medicine as dronabinol or nabilone are felt to be more useful for most conditions, however it is widely used in research into the potential therapeutic applications of cannabinoids.
Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of GABAergic inhibitory cell representing 95% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.
SH-SY5Y is a human derived cell line used in scientific research. The original cell line, called SK-N-SH, from which it was subcloned was isolated from a bone marrow biopsy taken from a four-year-old female with neuroblastoma. SH-SY5Y cells are often used as in vitro models of neuronal function and differentiation. They are adrenergic in phenotype but also express dopaminergic markers and, as such, have been used to study Parkinson's disease, neurogenesis, and other characteristics of brain cells.
The Gs alpha subunit is a subunit of the heterotrimeric G protein Gs that stimulates the cAMP-dependent pathway by activating adenylyl cyclase. Gsα is a GTPase that functions as a cellular signaling protein. Gsα is the founding member of one of the four families of heterotrimeric G proteins, defined by the alpha subunits they contain: the Gαs family, Gαi/Gαo family, Gαq family, and Gα12/Gα13 family. The Gs-family has only two members: the other member is Golf, named for its predominant expression in the olfactory system. In humans, Gsα is encoded by the GNAS complex locus, while Golfα is encoded by the GNAL gene.
Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred to as Gi alpha, Gαi, or Giα.
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.
The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.
Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.
The adenosine A2B receptor, also known as ADORA2B, is a G-protein coupled adenosine receptor, and also denotes the human adenosine A2b receptor gene which encodes it.
Cannabinoid receptor 1 (CB1), is a G protein-coupled cannabinoid receptor that in humans is encoded by the CNR1 gene. The human CB1 receptor is expressed in the peripheral nervous system and central nervous system. It is activated by endogenous cannabinoids called endocannabinoids, a group of retrograde neurotransmitters that include lipids, such as anandamide and 2-arachidonoylglycerol (2-AG); plant phytocannabinoids, such as docosatetraenoylethanolamide found in wild daga, the compound THC which is an active constituent of the psychoactive drug cannabis; and synthetic analogs of THC. CB1 is antagonized by the phytocannabinoid tetrahydrocannabivarin (THCV).
SCH-58261 is a drug which acts as a potent and selective antagonist for the adenosine receptor A2A, with more than 50x selectivity for A2A over other adenosine receptors. It has been used to investigate the mechanism of action of caffeine, which is a mixed A1 / A2A antagonist, and has shown that the A2A receptor is primarily responsible for the stimulant and ergogenic effects of caffeine, but blockade of both A1 and A2A receptors is required to accurately replicate caffeine's effects in animals. SCH-58261 has also shown antidepressant, nootropic and neuroprotective effects in a variety of animal models, and has been investigated as a possible treatment for Parkinson's disease.
The G protein-coupled inwardly rectifying potassium channels (GIRKs) are a family of lipid-gated inward-rectifier potassium ion channels which are activated (opened) by the signaling lipid PIP2 and a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs in turn release activated G-protein βγ- subunits (Gβγ) from inactive heterotrimeric G protein complexes (Gαβγ). Finally, the Gβγ dimeric protein interacts with GIRK channels to open them so that they become permeable to potassium ions, resulting in hyperpolarization of the cell membrane. G protein-coupled inwardly rectifying potassium channels are a type of G protein-gated ion channels because of this direct interaction of G protein subunits with GIRK channels. The activation likely works by increasing the affinity of the channel for PIP2. In high concentration PIP2 activates the channel absent G-protein, but G-protein does not activate the channel absent PIP2.
Surinabant (SR147778) is a cannabinoid receptor type 1 antagonist developed by Sanofi-Aventis. It is being investigated as a potential treatment for nicotine addiction, to assist smoking cessation. It may also be developed as an anorectic drug to assist with weight loss, however there are already several CB1 antagonists or inverse agonists on the market or under development for this application, so surinabant is at present mainly being developed as an anti-smoking drug, with possible application in the treatment of other addictive disorders such as alcoholism. Other potential applications such as treatment of ADHD have also been proposed.
A GPCR oligomer is a protein complex that consists of a small number of G protein-coupled receptors (GPCRs). It is held together by covalent bonds or by intermolecular forces. The subunits within this complex are called protomers, while unconnected receptors are called monomers. Receptor homomers consist of identical protomers, while heteromers consist of different protomers.
The D1–D2 dopamine receptor heteromer is a receptor heteromer consisting of D1 and D2 protomers.
Adenosine A2A receptor antagonists are a class of drugs that blocks adenosine at the adenosine A2A receptor. Notable adenosine A2A receptor antagonists include caffeine, theophylline and istradefylline.
References
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- ↑ Merriam-Webster Dictionary
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- ↑ Heldt SA, Ressler KJ (December 2007). "Forebrain and midbrain distribution of major benzodiazepine–sensitive GABAA receptor subunits in the adult C57 mouse as assessed with in situ hybridization". Neuroscience. 150 (2): 370–85. doi:10.1016/j.neuroscience.2007.09.008. PMC 2292345 . PMID 17950542.
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- ↑ Rashid AJ, So CH, Kong MM, Furtak T, El-Ghundi M, Cheng R, O'Dowd BF, George SR (January 2007). "D1–D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of Gq/11 in the striatum". Proceedings of the National Academy of Sciences of the United States of America. 104 (2): 654–9. Bibcode:2007PNAS..104..654R. doi: 10.1073/pnas.0604049104 . PMC 1766439 . PMID 17194762.
- ↑ Marcellino D, Ferré S, Casadó V, Cortés A, Le Foll B, Mazzola C, Drago F, Saur O, Stark H, Soriano A, Barnes C, Goldberg SR, Lluis C, Fuxe K, Franco R (September 2008). "Identification of Dopamine D1–D3 Receptor Heteromers: INDICATIONS FOR A ROLE OF SYNERGISTIC D1–D3 RECEPTOR INTERACTIONS IN THE STRIATUM". The Journal of Biological Chemistry. 283 (38): 26016–25. doi: 10.1074/jbc.M710349200 . PMC 2533781 . PMID 18644790.
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- ↑ Zezula J, Freissmuth M (March 2008). "The A2A-adenosine receptor: a GPCR with unique features?". British Journal of Pharmacology . 153 Suppl 1 (S1): S184–90. doi:10.1038/sj.bjp.0707674. PMC 2268059 . PMID 18246094.
- ↑ Marcellino D, Carriba P, Filip M, Borgkvist A, Frankowska M, Bellido I, Tanganelli S, Müller CE, Fisone G, Lluis C, Agnati LF, Franco R, Fuxe K (April 2008). "Antagonistic cannabinoid CB1/dopamine D2 receptor interactions in striatal CB1/D2 heteromers. A combined neurochemical and behavioral analysis". Neuropharmacology. 54 (5): 815–23. doi:10.1016/j.neuropharm.2007.12.011. PMID 18262573. S2CID 195685369.
- ↑ Carriba P, Navarro G, Ciruela F, Ferré S, Casadó V, Agnati L, Cortés A, Mallol J, Fuxe K, Canela EI, Lluis C, Franco R (2008). "Detection of heteromerization of more than two proteins by sequential BRET-FRET". Nature Methods. 5 (8): 727–33. doi:10.1038/nmeth.1229. PMID 18587404. S2CID 5175118.
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- ↑ Franco R, Casadó V, Cortés A, Pérez-Capote K, Mallol J, Canela E, Ferré S, Lluis C (August 2008). "Novel pharmacological targets based on receptor heteromers". Brain Research Reviews. 58 (2): 475–82. doi:10.1016/j.brainresrev.2008.06.002. PMID 18620000. S2CID 41153163.
- ↑ Fuxe K, Marcellino D, Woods AS, Giuseppina L, Antonelli T, Ferraro L, Tanganelli S, Agnati LF (January 2009). "Integrated signaling in heterodimers and receptor mosaics of different types of GPCRs of the forebrain: relevance for schizophrenia". Journal of Neural Transmission. 116 (8): 923–39. doi:10.1007/s00702-008-0174-9. PMC 2953764 . PMID 19156349.
- ↑ Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KD, Pin JP, Volkow ND, Waldhoer M, Woods AS, Franco R (March 2009). "Building a new conceptual framework for receptor heteromers". Nature Chemical Biology. 5 (3): 131–4. doi:10.1038/nchembio0309-131. PMC 2681085 . PMID 19219011.