The class C G-protein-coupled receptors are a class of G-protein coupled receptors that include the metabotropic glutamate receptors and several additional receptors (Brauner-Osborne H et al, 2007). Family C GPCRs have a large extracellular N-terminus which binds the orthosteric (endogenous) ligand. The shape of this domain is often likened to a clam. Several allosteric ligands to these receptors have been identified and these bind within the seven transmembrane region.
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Conn PJ, Pin JP.; ''Pharmacology and functions of metabotropic glutamate receptors.''; PubMedEurope PMCScholia
Kifor O, Diaz R, Butters R, Brown EM.; ''The Ca2+-sensing receptor (CaR) activates phospholipases C, A2, and D in bovine parathyroid and CaR-transfected, human embryonic kidney (HEK293) cells.''; PubMedEurope PMCScholia
Emile L, Mercken L, Apiou F, Pradier L, Bock MD, Menager J, Clot J, Doble A, Blanchard JC.; ''Molecular cloning, functional expression, pharmacological characterization and chromosomal localization of the human metabotropic glutamate receptor type 3.''; PubMedEurope PMCScholia
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Kaupmann K, Schuler V, Mosbacher J, Bischoff S, Bittiger H, Heid J, Froestl W, Leonhard S, Pfaff T, Karschin A, Bettler B.; ''Human gamma-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K+ channels.''; PubMedEurope PMCScholia
Bräuner-Osborne H, Wellendorph P, Jensen AA.; ''Structure, pharmacology and therapeutic prospects of family C G-protein coupled receptors.''; PubMedEurope PMCScholia
White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH.; ''Heterodimerization is required for the formation of a functional GABA(B) receptor.''; PubMedEurope PMCScholia
Flor PJ, Lukic S, Rüegg D, Leonhardt T, Knöpfel T, Kuhn R.; ''Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 4.''; PubMedEurope PMCScholia
Laurie DJ, Schoeffter P, Wiederhold KH, Sommer B.; ''Cloning, distribution and functional expression of the human mGlu6 metabotropic glutamate receptor.''; PubMedEurope PMCScholia
Mizuno N, Itoh H.; ''Functions and regulatory mechanisms of Gq-signaling pathways.''; PubMedEurope PMCScholia
Li X, Staszewski L, Xu H, Durick K, Zoller M, Adler E.; ''Human receptors for sweet and umami taste.''; PubMedEurope PMCScholia
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Minakami R, Katsuki F, Yamamoto T, Nakamura K, Sugiyama H.; ''Molecular cloning and the functional expression of two isoforms of human metabotropic glutamate receptor subtype 5.''; PubMedEurope PMCScholia
Hildebrandt JD.; ''Role of subunit diversity in signaling by heterotrimeric G proteins.''; PubMedEurope PMCScholia
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Wellendorph P, Bräuner-Osborne H.; ''Molecular cloning, expression, and sequence analysis of GPRC6A, a novel family C G-protein-coupled receptor.''; PubMedEurope PMCScholia
Wellendorph P, Hansen KB, Balsgaard A, Greenwood JR, Egebjerg J, Bräuner-Osborne H.; ''Deorphanization of GPRC6A: a promiscuous L-alpha-amino acid receptor with preference for basic amino acids.''; PubMedEurope PMCScholia
Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M.; ''The molecular receptive ranges of human TAS2R bitter taste receptors.''; PubMedEurope PMCScholia
Wu S, Wright RA, Rockey PK, Burgett SG, Arnold JS, Rosteck PR, Johnson BG, Schoepp DD, Belagaje RM.; ''Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells.''; PubMedEurope PMCScholia
Desai MA, Burnett JP, Mayne NG, Schoepp DD.; ''Cloning and expression of a human metabotropic glutamate receptor 1 alpha: enhanced coupling on co-transfection with a glutamate transporter.''; PubMedEurope PMCScholia
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The classical signalling mechanism for G alpha (i) is inhibition of the cAMP dependent pathway through inhibition of adenylate cyclase (Dessauer C W et al. 2002). Decreased production of cAMP from ATP results in decreased activity of cAMP-dependent protein kinases. Other functions of G alpha (i) includes activation of the protein tyrosine kinase c-Src (Ma Y C et al. 2000). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (i) (Soundararajan et al. 2008).
The classic signalling route for G alpha (q) is activation of phospholipase C beta thereby triggering phosphoinositide hydrolysis, calcium mobilization and protein kinase C activation. This provides a path to calcium-regulated kinases and phosphatases, GEFs, MAP kinase cassettes and other proteins that mediate cellular responses ranging from granule secretion, integrin activation, and aggregation in platelets. Gq participates in many other signalling events including direct interaction with RhoGEFs that stimulate RhoA activity and inhibition of PI3K. Both in vitro and in vivo, the G-protein Gq seems to be the predominant mediator of the activation of platelets. Moreover, G alpha (q) can stimulate the activation of Burton tyrosine kinase (Ma Y C et al. 1998). Regulator of G-protein Signalling (RGS) proteins can regulate the activity of G alpha (z) (Soundararajan M et al. 2008).
Humans can perceive thousands of compounds as bitter-tasting despite having around 25 bitter taste receptors, encoded by the Taste 2 Receptor (TAS2R or T2R) gene family (Adler et al. 2000, Chandrashekar et al. 2000, Matsunami et al. 2000), which signal via the Gi family G-protein Gustducin (Caicedo et al. 2003). Some receptors recognize only a few agonists while others have moderate or broad agonist ranges (Meyerhof et al. 2009). Although there is no clear correlation between bitterness and toxicity (Glendinning 1994), it is generally believed that this sense prevents mammals from ingesting potentially harmful food constituents.
Bitter compounds are numerous, esitimates for natural bitter compounds are in the tens of thousands. They are structurally diverse, including hydroxy fatty acids, fatty acids, peptides, amino acids, amines, amides, azacycloalkanes, N-heterocyclic compounds, ureas, thioureas, carbamides, esters, lactones, carbonyl compounds, phenols, crown ethers, terpenoids, secoiridoids, alkaloids, glycosides, flavonoids, steroids, halogenated or acetylated sugars, and metal ions (DuBois et al. 2008). The representative set of compounds in this reaction are taken from Table 1 in Meyerhof et al. (2009).
The metabotropic glutamate receptors (mGluRs) are members of the group C family of G-protein-coupled receptors (GPCRs) (Pin JP et al, 1995; Conn PJ and Pin JP, 1997). Metabotropic glutamate receptors are characterized by a large N-terminal extracellular domain of approximately 560 amino acids which possesses the glutamate binding domain and confers selectivity for agonists. There are eight mGluRs, 1-8 (Desai MA et al, 1995; Flor PJ et al, 1995; Emile L. et al, 1996; Flor PJ et al, 1995b; Minakami R et al, 1994; Laurie DJ et al, 1997; Wu S et al, 1998 respectively). They can be subdivided into 'groups' according to their sequence homology, signal transduction mechanisms and pharmacological properties. Group I contains mGluR1 and 5; Group II contains mGluR2 and 3; Group III contains mGluR4,6,7 and 8 (Nakanishi S, 1992). Group I receptors activate PLC downstream via coupling to Gq/11. Groups II and III inhibit adenylyl cyclase via coupling to Gi. Like all glutamate receptors, mGluRs bind to glutamate, an amino acid that functions as an excitatory neurotransmitter. Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system.
Gamma-aminobutyric acid (GABA) is the chief inhibitory neurotransmitter in the mammalian central nervous system. GABA exerts its effects through two ligand-gated channels and a the GPCR GABAB (Kaupmann K et al, 1998), which acts through G proteins to regulate potassium and calcium channels. GABAB can only bind GABA once it forms a heterodimer composed of the GABABR1 and GABABR2 receptors (White JH et al, 1998). The effects of this dimer are mediated by coupling to the G protein alpha i subunit, which inhibits adenylyl cyclase (Odagaki & Koyama 2001).
The parathyroid glands play a role in ion homeostasis by sensing small changes in extracellular Ca2+ ion concentration. These glands express a cell surface receptor, calcium-sensing receptors (CaR) (Garrett JE et al, 1995) that is activated by increases in the concentration of extracellular calcium and by a variety of other cations. CaR serves as the primary physiological regulator of parathyroid hormone (PTH) secretion. CaR contributes to regulation of systemic calcium homeostasis by activation of Gq- (Kifor O et al, 1997) and Gi-linked (Kifor O et al, 2001) signaling pathways in the parathyroid glands, kidney and intestine.
G-protein coupled receptor family C group 6 member A (GPRC6A, GPCR33) (Wellendorph P and Brauner-Osborne H, 2004) is a receptor that functions as a sensor for both L-amino acids and extracellular concentration of calcium ions. GPRC6A is a promiscuous L-alpha-amino acid receptor but has preference for the basic amino-acids L-Arg, L-Lys and L-ornithine (Wellendorph P et al, 2005). The effects of this receptor are mediated by coupling to the G protein alpha q/11 subunit, which activates a phosphatidylinositol-calcium second messenger system.
A dimer of T1R2 and T1R3 receptors responds to diverse stimuli associated with the human sense of sweet taste, such as sucrose, d-tryptophan, aspartame, and saccharin. Signaling occurs via the Gi family G-protein Gustducin (Caicedo et al. 2003).
Dimers of the T1R1 and T1R3 receptors responds to the umami taste stimulus L-glutamate, signaling via the Gi family G-protein Gustducin (Caicedo et al. 2003).
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receptor:GPRC6A
ligandsAnnotated Interactions
receptor:GPRC6A
ligandsBitter compounds are numerous, esitimates for natural bitter compounds are in the tens of thousands. They are structurally diverse, including hydroxy fatty acids, fatty acids, peptides, amino acids, amines, amides, azacycloalkanes, N-heterocyclic compounds, ureas, thioureas, carbamides, esters, lactones, carbonyl compounds, phenols, crown ethers, terpenoids, secoiridoids, alkaloids, glycosides, flavonoids, steroids, halogenated or acetylated sugars, and metal ions (DuBois et al. 2008). The representative set of compounds in this reaction are taken from Table 1 in Meyerhof et al. (2009).
Like all glutamate receptors, mGluRs bind to glutamate, an amino acid that functions as an excitatory neurotransmitter. Glutamate is the most abundant excitatory neurotransmitter in the mammalian nervous system.