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G proteins,also known as guanine nucleotide-binding proteins,are a family of proteins that act as molecular switches inside cells,and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP,they are 'on',and,when they are bound to GDP,they are 'off'. G proteins belong to the larger group of enzymes called GTPases.
An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast,an antagonist blocks the action of the agonist,while an inverse agonist causes an action opposite to that of the agonist.
Functional selectivity is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity,or biased signaling,is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists,such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs,or those at opioid receptors that mediate pain,show potential at various receptor families to increase beneficial properties while reducing side effects. For example,pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example,a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.
In biology,cell signaling is the process by which a cell interacts with itself,other cells,and the environment. Cell signaling is a fundamental property of all cellular life in prokaryotes and eukaryotes.
A receptor activated solely by a synthetic ligand (RASSL) or designer receptor exclusively activated by designer drugs (DREADD),is a class of artificially engineered protein receptors used in the field of chemogenetics which are selectively activated by certain ligands. They are used in biomedical research,in particular in neuroscience to manipulate the activity of neurons.
The 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor,but has several intracellular locations.
P2Y receptors are a family of purinergic G protein-coupled receptors,stimulated by nucleotides such as adenosine triphosphate,adenosine diphosphate,uridine triphosphate,uridine diphosphate and UDP-glucose.To date,8 P2Y receptors have been cloned in humans:P2Y1,P2Y2,P2Y4,P2Y6,P2Y11,P2Y12,P2Y13 and P2Y14.
EGF-like module-containing mucin-like hormone receptor-like 1 also known as F4/80 is a protein encoded by the ADGRE1 gene. EMR1 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
EGF-like module-containing mucin-like hormone receptor-like 2 also known as CD312 is a protein encoded by the ADGRE2 gene. EMR2 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
EGF-like module-containing mucin-like hormone receptor-like 3 is a protein encoded by the ADGRE3 gene. EMR3 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine,5-HT). Like all 5-HT2 receptors,the 5-HT2B receptor is Gq/G11-protein coupled,leading to downstream activation of phospholipase C.
5-Hydroxytryptamine (serotonin) receptor 5A,also known as HTR5A,is a protein that in humans is encoded by the HTR5A gene. Agonists and antagonists for 5-HT receptors,as well as serotonin uptake inhibitors,present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions,and 5-HT receptors are also associated with neural changes.
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G protein-coupled receptor 126 also known as VIGR and DREG is a protein encoded by the ADGRG6 gene. GPR126 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
G protein-coupled receptor 128 is a protein encoded by the ADGRG7 gene. GPR128 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
G protein-coupled receptor 112 is a protein encoded by the ADGRG4 gene. GPR112 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
G protein-coupled receptor 114 is a protein encoded by the ADGRG5 gene. GPR114 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
G-protein coupled receptor 97 also known as adhesion G protein-coupled receptor G3 (ADGRG3) is a protein that in humans is encoded by the ADGRG3 gene. GPR97 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
G protein-coupled receptor 56 also known as TM7XN1 is a protein encoded by the ADGRG1 gene. GPR56 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
Chemogenetics is the process by which macromolecules can be engineered to interact with previously unrecognized small molecules. Chemogenetics as a term was originally coined to describe the observed effects of mutations on chalcone isomerase activity on substrate specificities in the flowers of Dianthus caryophyllus. This method is very similar to optogenetics;however,it uses chemically engineered molecules and ligands instead of light and light-sensitive channels known as opsins.
References
- ↑ "Bryan Roth, MD, PhD". Pharmacology. Retrieved 2021-10-16.
- ↑ Roth, Bryan. "Biographical Sketch" (PDF). UNC School of Medicine . Archived (PDF) from the original on 2021-10-16. Retrieved 16 October 2021.
- ↑ Roth, Bryan. "Biographical Sketch" (PDF). UNC School of Medicine . Archived (PDF) from the original on 2021-10-16. Retrieved 16 October 2021.
- ↑ Wacker D, Wang S, McCorvy JD, Betz RM, Venkatakrishnan, AJ, Levit A, Lansu K, Schools Z, Che T, Nichols DE, Shoichet BK, Dror RD, and Roth BL: Crystal structure of an LSD-bound human serotonin receptor. Cell 168: 377-389
- ↑ Kim...and Roth, Cell 182: 1574-1588, 2020
- ↑ English JG. Olsen, RHJ, Lansu K, Patel M, White K, Cockrell AS, Sing D, Strachan RT, Wacker D and Roth BL. VEGAS as a platform for facile directed evolution in mammalian cells. Cell 178: 748-761, 2019
- ↑ BN Armbruster, X Li, S Herlitzer, M Pausch and BL Roth: Evolving the lock to fit the key to create a family of GPCRs potently activated by an inert ligand. Proc Natl Acad Sci 2007 Mar 20;104(12):5163-8 (Highlighted on Cover) PMID 17350345
- ↑ "Post by Former NIMH Director Thomas Insel: Best of 2014". National Institute of Mental Health . Archived from the original on 2016-12-15.
- ↑ Berndt, J., & Wong, W. (2015, January 06). 2014: Signaling Breakthroughs of the Year. https://www.science.org/doi/full/10.1126/scisignal.aaa4696
- ↑ Adler, E. (2017, January 03). 2016: Signaling Breakthroughs of the Year. Retrieved April 16, 2021, from https://www.science.org/doi/10.1126/scisignal.aam5681
- ↑ Voices of chemical biology. Nature Chemical Biology 11, 446–447 (2015). https://doi.org/10.1038/nchembio.1845
- ↑ Insel, Thomas (23 December 2011). "NIMH's top 10 research advances of 2011". National Institute of Mental Health . Archived from the original on 2012-01-18. Retrieved 27 March 2023.
- ↑ "Top scientific breakthroughs of 2009". Wired . December 2009.
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