Activation of Family C G-protein-coupled Receptors by the Tripeptide Glutathione

The Family C G-protein-coupled receptors include the metabotropic glutamate receptors, the γ-aminobutyric acid, type B (GABAB) receptor, the calcium-sensing receptor (CaSR), which participates in the regulation of calcium homeostasis in the body, and a diverse group of sensory receptors that encompass the amino acid-activated fish 5.24 chemosensory receptor, the mammalian T1R taste receptors, and the V2R pheromone receptors. A common feature of Family C receptors is the presence of an amino acid binding site. In this study, a preliminary in silico analysis of the size and shape of the amino acid binding pocket in selected Family C receptors suggested that some members of this family could accommodate larger ligands such as peptides. Subsequent screening and docking experiments identified GSH as a potential ligand or co-ligand at the fish 5.24 receptor and the rat CaSR. These in silico predictions were confirmed using an [3H]GSH radioligand binding assay and a fluorescence-based functional assay performed on wild-type and chimeric receptors. Glutathione was shown to act as an orthosteric agonist at the 5.24 receptor and as a potent enhancer of calcium-induced activation of the CaSR. Within the mammalian receptors, this effect was specific to the CaSR because GSH neither directly activated nor potentiated other Family C receptors including GPRC6A (the putative mammalian homolog of the fish 5.24 receptor), the metabotropic glutamate receptors, or the GABAB receptor. Our findings reveal a potential new role for GSH and suggest that this peptide may act as an endogenous modulator of the CaSR in the parathyroid gland where this receptor is known to control the release of parathyroid hormone, and in other tissues such as the brain and gastrointestinal tract where the role of the calcium receptor appears to subserve other, as yet unknown, physiological functions. The Family C G-protein-coupled receptors include the metabotropic glutamate receptors, the γ-aminobutyric acid, type B (GABAB) receptor, the calcium-sensing receptor (CaSR), which participates in the regulation of calcium homeostasis in the body, and a diverse group of sensory receptors that encompass the amino acid-activated fish 5.24 chemosensory receptor, the mammalian T1R taste receptors, and the V2R pheromone receptors. A common feature of Family C receptors is the presence of an amino acid binding site. In this study, a preliminary in silico analysis of the size and shape of the amino acid binding pocket in selected Family C receptors suggested that some members of this family could accommodate larger ligands such as peptides. Subsequent screening and docking experiments identified GSH as a potential ligand or co-ligand at the fish 5.24 receptor and the rat CaSR. These in silico predictions were confirmed using an [3H]GSH radioligand binding assay and a fluorescence-based functional assay performed on wild-type and chimeric receptors. Glutathione was shown to act as an orthosteric agonist at the 5.24 receptor and as a potent enhancer of calcium-induced activation of the CaSR. Within the mammalian receptors, this effect was specific to the CaSR because GSH neither directly activated nor potentiated other Family C receptors including GPRC6A (the putative mammalian homolog of the fish 5.24 receptor), the metabotropic glutamate receptors, or the GABAB receptor. Our findings reveal a potential new role for GSH and suggest that this peptide may act as an endogenous modulator of the CaSR in the parathyroid gland where this receptor is known to control the release of parathyroid hormone, and in other tissues such as the brain and gastrointestinal tract where the role of the calcium receptor appears to subserve other, as yet unknown, physiological functions. Free amino acids act within the large extracellular ligand binding domains of Family C G-protein-coupled receptors as either the direct acting orthosteric agonists or as allosteric modulators. Glutamate, and the glutamate metabolite GABA, are the endogenous ligands at the metabotropic glutamate receptors (mGluRs) 3The abbreviations used are: mGluR, metabotropic glutamate receptor; CaSR, calcium-sensing receptor; HEK, human embryonic kidney; GABAA and GABAB, γ-aminobutyric acid, types A and B, respectively; HPLC, high performance liquid chromatography. 3The abbreviations used are: mGluR, metabotropic glutamate receptor; CaSR, calcium-sensing receptor; HEK, human embryonic kidney; GABAA and GABAB, γ-aminobutyric acid, types A and B, respectively; HPLC, high performance liquid chromatography. and the GABAB receptor, respectively. In contrast to the restricted activation of the mGluRs and the GABAB receptor by glutamate and GABA, other Family C receptors can be activated by multiple amino acids. The fish 5.24 chemosensory receptor, which is expressed in several sensory organs and is thought to play a role in feeding and navigation, can be activated by most amino acids (1Speca D.J. Lin D.M. Sorensen P.W. Isacoff E.Y. Ngai J. Dittman A.H. Neuron. 1999; 23: 487-498Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). A similar, albeit non-identical, spectrum of amino acid activation is also an intrinsic property of GPRC6A, the putative mammalian homolog of the 5.24 receptor (2Kuang D. Yao Y. Lam J. Tsushima R.G. Hampson D.R. J. Neurochem. 2005; 93: 383-391Crossref PubMed Scopus (118) Google Scholar, 3Wellendorph P. Hansen K.B. Balsgaard A. Greenwood J.R. Egebjerg J. Brauner-Osborne H. Mol. Pharmacol. 2005; 67: 589-597Crossref PubMed Scopus (170) Google Scholar), and the T1R1/T1R3 heteromeric taste receptor (4Li X. Staszewski L. Xu H. Durick K. Zoller M. Adler E. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 4692-4696Crossref PubMed Scopus (1081) Google Scholar). Amino acids also allosterically regulate the activity of the calcium-sensing receptor (CaSR), another member of the Family C receptors. Although calcium is considered the primary endogenous ligand, calcium-induced responses mediated by the CaSR are enhanced in the presence of amino acids (5Conigrave A.D. Quinn S.J. Brown E.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4814-4819Crossref PubMed Scopus (407) Google Scholar). The CaSR possesses an amino acid binding site in the extracellular domain analogous to the glutamate and GABA sites in the mGluR and GABAB receptors (6Mun H.C. Culverston E.L. Franks A.H. Collyer C.A. Clifton-Bligh R.J. Conigrave A.D. J. Biol. Chem. 2005; 280: 29067-29072Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 7Zhang Z. Qiu W. Quinn S.J. Conigrave A.D. Brown E.M. Bai M. J. Biol. Chem. 2002; 277: 33727-33735Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar). The physiological importance of amino acid modulation of the CaSR has been demonstrated in human parathyroid cells where amino acids have been shown to enhance the CaSR-mediated suppression of parathyroid hormone release (8Conigrave A.D. Mun H.C. Delbridge L. Quinn S.J. Wilkinson M. Brown E.M. J. Biol. Chem. 2004; 279: 38151-38159Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). In addition to amino acids and cations, several peptides have been reported to activate or modulate Family C receptors. For example, the endogenous dipeptide N-acetylaspartylglutamate has been reported to activate mGluR3 (9Neale J.H. Bzdega T. Wroblewska B. J. Neurochem. 2000; 75: 443-452Crossref PubMed Scopus (288) Google Scholar), and β amyloid peptides have been shown to modulate intracellular calcium levels induced by activation of the CaSR (10Ye C. Ho-Pao C.L. Kanazirska M. Quinn S. Rogers K. Seidman C.E. Seidman J.G. Brown E.M. Vassilev P.M. J. Neurosci. Res. 1997; 47: 547-554Crossref PubMed Scopus (113) Google Scholar). However, the β amyloid peptides appear to affect CaSR activity indirectly via stimulation of calcium permeable ion channels (10Ye C. Ho-Pao C.L. Kanazirska M. Quinn S. Rogers K. Seidman C.E. Seidman J.G. Brown E.M. Vassilev P.M. J. Neurosci. Res. 1997; 47: 547-554Crossref PubMed Scopus (113) Google Scholar, 11Yano S. Brown E.M. Chattopadhyay N. Cell 2004; PubMed Scopus Google Scholar). The activity of some members of the V2R of Family C pheromone receptors may also be by peptides. Although most of the endogenous ligands for the V2R receptors are yet H. S. K. K. 2005; PubMed Scopus Google have demonstrated that peptides the gland of activate activity in V2R in the where appear to as and However, on are mediated by direct the peptides and V2R receptors to be on that peptides can activate some Family C receptors, an in silico of the amino acid binding of Family C G-protein-coupled receptors. analysis of the size and shape of the amino acid binding of selected Family C receptors suggested that of the receptors and that some of the binding may be large to accommodate peptides. Subsequent screening and docking experiments identified the GSH as a potential ligand or co-ligand at the fish 5.24 receptor and the rat CaSR. in silico receptor were expressed in human embryonic cells and for to be activated or potentiated by Our that GSH within the extracellular ligand binding domain of the 5.24 chemosensory receptor and the CaSR to directly activate and respectively. These findings reveal for GSH at G-protein-coupled receptors and suggest that this may be a endogenous modulator of the CaSR. and and were The of the GSH was confirmed by analysis and via activity was The was and the was were and of the wild-type 5.24 receptor, CaSR, and GPRC6A were using the of the extracellular domain of rat as a using of the A. J. Mol. Biol. PubMed Scopus Google as by and Hampson M. Hampson D.R. Chem. 2005; PubMed Scopus Google Scholar). was used to and the The most potent amino acid ligand for receptor for 5.24 receptor and GPRC6A and for the was the amino acid binding These ligands were in the to the in the binding in and the for the ligands were the of in S. D. P. Scopus Google Scholar). The of was performed using in the presence of as by and Hampson M. Hampson D.R. Chem. 2005; PubMed Scopus Google Scholar). In the the was for the to the in the the ligand and receptor in the binding the was by another of the was for by the on the to For ligand peptide and were and using to to of the peptide and to the in GSH were to The ligand were the binding as within of the ligand, using the docking M. B. T. J. Mol. Biol. PubMed Scopus Google as in The was selected on the the in the of and rat CaSR in the was as by M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), and the was as by J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The wild-type fish 5.24 (1Speca D.J. Lin D.M. Sorensen P.W. Isacoff E.Y. Ngai J. Dittman A.H. Neuron. 1999; 23: 487-498Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar), the rat and receptors Y. M. T. S. Neuron. Full Text PDF PubMed Scopus Google Scholar), and the GABAB and and the GPRC6A receptor (2Kuang D. Yao Y. Lam J. Tsushima R.G. Hampson D.R. J. Neurochem. 2005; 93: 383-391Crossref PubMed Scopus (118) Google were the A of the CaSR at was by using wild-type rat CaSR as a The were as The a site and of the an site and a The was by and by The 5.24 receptor was as D. Yao Y. M. N. Hampson D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The were cells using the The cells were in For the receptors, the was and the the receptors was for analysis The for were as by Yao Y. N. Hampson D.R. J. Neurochem. PubMed Scopus Google Scholar). were either an or an The the extracellular domain of 5.24 to and the and of GPRC6A was as by (2Kuang D. Yao Y. Lam J. Tsushima R.G. Hampson D.R. J. Neurochem. 2005; 93: 383-391Crossref PubMed Scopus (118) Google Scholar). The chimeric receptor the extracellular domain of GPRC6A to and the and intracellular domains of 5.24 receptor was by The of was performed of and and The was performed using and the was and used to the in the (2Kuang D. Yao Y. Lam J. Tsushima R.G. Hampson D.R. J. Neurochem. 2005; 93: 383-391Crossref PubMed Scopus (118) Google Scholar). were to that the was used in the and of 5.24 receptor and CaSR and radioligand binding assay were performed as D. Yao Y. M. N. Hampson D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the for or cells was and at for at and of the was at in in binding The were at for at and to radioligand binding or at The radioligand binding assay was in a of For the 5.24 receptor, of was of of [3H]GSH and of GSH For CaSR, the assay was the as for the 5.24 receptor, the assay The was for on of and of were to The was on for and at for The was and in of The were on a liquid analysis of the 5.24 receptor, and the and the functional assay was performed as D. Yao Y. M. N. Hampson D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). For analysis of the CaSR and the the was used several The for and was a and For activation of the CaSR and the cells were to an or of the and the responses were on a as by D. Yao Y. M. N. Hampson D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The was used to and the A of the of Family C G-protein-coupled of the extracellular domains of several of Family C receptors including the CaSR, the 5.24 receptor, and GPRC6A were using the of the of as the A of the putative amino acid binding of receptors is shown in the shape and size of the in the receptors. In of the the to the was GPRC6A 5.24 receptor CaSR. In silico docking of the ligands for and GPRC6A a within the binding In docking of of the amino acid ligands at the 5.24 receptor and the CaSR that the of receptors by the amino to the that larger ligands such as peptides may at some Family C receptors. in silico docking analysis of several endogenous peptides suggested that GSH could be in the 5.24 amino acid binding pocket in a that of of GSH and in the amino acid binding pocket of the 5.24 receptor. The is as the of ligands are The ligand were selected using the within the of of the 5.24 by the of GSH to act as an agonist at the fish 5.24 receptor, cells were a and in a functional assay the 5.24 receptor and GPRC6A to the family of and activate C agonist responses to receptors can be by the release of intracellular calcium in cells the which was used as a and GSH induced responses in cells the 5.24 receptor; the for and GSH at the 5.24 receptor were and In addition to GSH the of and of and and a were also on the 5.24 receptor. in were also in cells the 5.24 receptor to and and and for the 5.24 receptor in the that were In neither nor the dipeptide effect on the 5.24 receptor. In contrast to the 5.24 receptor, at of to activate GPRC6A, the putative mammalian homolog of the 5.24 receptor. that GSH as an agonist at 5.24 GPRC6A, and to that the of GSH on the 5.24 receptor were mediated by in the extracellular receptor A of the extracellular domain of GPRC6A to the and of 5.24 was and activated this receptor an activation was GSH at of to The (2Kuang D. Yao Y. Lam J. Tsushima R.G. Hampson D.R. J. Neurochem. 2005; 93: 383-391Crossref PubMed Scopus (118) Google the extracellular ligand binding domain of the 5.24 receptor to the and of GPRC6A was also Although GSH effect on the GPRC6A receptor at to GSH activated the an that GSH as an agonist at the 5.24 receptor at putative mammalian GPRC6A, and that the on 5.24 are mediated via the extracellular amino acid binding domain of the receptor. directly the binding of GSH to the 5.24 receptor, a radioligand binding assay using experiments on cells the presence of a high of [3H]GSH to in cells using and D. Yao Y. M. N. Hampson D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). this the of the 5.24 receptor in which the extracellular domain is expressed of the and domains as the of cells D. Yao Y. M. N. Hampson D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). [3H]GSH binding was in the cells the 5.24 receptor, binding was in the cells experiments were on the extracellular domain of the 5.24 receptor. experiments using [3H]GSH and of GSH an of the radioligand binding experiments on the 5.24 receptor and the chimeric receptor confirmed the that GSH was via the extracellular ligand binding a of in the putative amino acid binding pocket of the 5.24 receptor were to the docking of GSH in the binding site. The 5.24 was used as a for for and the were in the calcium release The that and in the 5.24 receptor the amino group of GSH and a the group of responses were the and for or GSH at to The a for wild-type receptor, GSH a at These suggested that the amino and of glutamate within the GSH in the receptor that the amino and of for wild-type and 5.24 in a new on the GSH the 5.24 amino acid pocket that the group of in GSH either or of the receptor. The an for and GSH that was to the wild-type 5.24 receptor, was The the for as the wild-type receptor, this a in for GSH the wild-type receptor the that the group in the of GSH and Glutathione the of the CaSR that the amino acid binding pocket be large to accommodate GSH or However, responses were in cells the CaSR in the calcium release assay to GSH or at to that GSH the CaSR as large amino acids such as and (5Conigrave A.D. Quinn S.J. Brown E.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4814-4819Crossref PubMed Scopus (407) Google Scholar, A.D. Mun H.C. Delbridge L. Quinn S.J. Wilkinson M. Brown E.M. J. Biol. Chem. 2004; 279: 38151-38159Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). amino acids have been shown to the suppression of the of parathyroid hormone human parathyroid and the for this effect is calcium (8Conigrave A.D. Mun H.C. Delbridge L. Quinn S.J. Wilkinson M. Brown E.M. J. Biol. Chem. 2004; 279: 38151-38159Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). in the experiments reported calcium were the cells were in calcium and to an to activate the receptor the of the in was to or the responses were by and the responses by calcium experiments were performed using the the for and were and that GSH and are potent of the calcium induced responses of the CaSR. in the was in the presence of the for calcium in the of GSH was was in the presence of or GSH A to was the CaSR in the presence of some amino acids (5Conigrave A.D. Quinn S.J. Brown E.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4814-4819Crossref PubMed Scopus (407) Google Scholar). The of GSH on the CaSR via the of GSH were also on a chimeric receptor, which the extracellular domain of CaSR and the and domains of the receptor, has been shown to a wild-type CaSR for calcium albeit responses J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the GSH and potentiated the calcium-induced responses on the receptor; the were and for GSH and that GSH via the extracellular of the CaSR, a of rat CaSR analogous to the 5.24 receptor was and [3H]GSH binding was on the the CaSR. specific [3H]GSH binding was in the of assay in the presence of specific [3H]GSH binding was in cells the the of specific to on CaSR was that on GSH [3H]GSH binding an the [3H]GSH binding and the the demonstrated that GSH within the extracellular domain of the CaSR. GSH Family C G-protein-coupled addition to the 5.24 receptor, GPRC6A, and the CaSR, also GSH could activate and receptors Y. M. T. S. Neuron. Full Text PDF PubMed Scopus Google and mGluRs in the functional fluorescence-based to cells were the and cells were the to the of to stimulation of C Y. N. Hampson D.R. J. Neurochem. PubMed Scopus Google Scholar, J. S. S. J. Mol. Pharmacol. Google Scholar, E. M. Yao Y. L. T. Hampson D.R. Mol. Pharmacol. 2004; PubMed Scopus Google Scholar). activation of receptors by activation by GSH was at of to nor was of the responses Glutathione was also on the GABAB receptor. For experiments the and were the chimeric activation of the receptor was GABA GSH responses at of GABA for the that GSH as an agonist and of G-protein-coupled receptors. The peptide is an orthosteric agonist at the fish 5.24 amino acid-activated chemosensory receptor and a potent enhancer of the mammalian CaSR. The of GSH to be Family C receptors including GPRC6A, the putative mammalian homolog of the 5.24 receptor, the and the GABAB receptor were neither directly activated nor potentiated by the this restricted spectrum of GSH activation Family C receptors was a on an in silico which that the within the binding of and GPRC6A was that of the CaSR and the 5.24 receptor The of the and GPRC6A the binding of large such as is that the and GSH activation of 5.24 and GPRC6A that GPRC6A is the mammalian homolog of the 5.24 receptor (2Kuang D. Yao Y. Lam J. Tsushima R.G. Hampson D.R. J. Neurochem. 2005; 93: 383-391Crossref PubMed Scopus (118) Google Scholar, 3Wellendorph P. Hansen K.B. Balsgaard A. Greenwood J.R. Egebjerg J. Brauner-Osborne H. Mol. Pharmacol. 2005; 67: 589-597Crossref PubMed Scopus (170) Google Scholar, Mol. Pharmacol. 2005; 67: PubMed Scopus Google Scholar). that GPRC6A, and the CaSR several such as activation or by and the activation or by several amino acids. the in the 5.24 receptor and GPRC6A and 5.24 the rat CaSR is (2Kuang D. Yao Y. Lam J. Tsushima R.G. Hampson D.R. J. Neurochem. 2005; 93: 383-391Crossref PubMed Scopus (118) Google Scholar). the that a of the and of members of a receptor The that specific [3H]GSH binding was in the of cells a the extracellular domain of the 5.24 receptor, the of the chimeric receptors, demonstrated that GSH to a site within the extracellular ligand binding domain and in the A analysis the of in silico peptide and the of a of in the binding the of GSH in the 5.24 receptor binding Amino acid ligands to Family C receptors in via the amino and of the ligands and a of in the binding In the of the group the of the glutamate is used to the peptide the in the the amino and on the glutamate in GSH this in the peptide to the the of in the binding pocket that the binding of amino acid However, the 5.24 amino acid ligand, where the in a D. Yao Y. M. N. Hampson D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, P. J. Ngai J. J. Neurosci. 2004; PubMed Scopus Google Scholar), docking experiments GSH suggest that the peptide may in a the in GSH the the of the 5.24 binding pocket are this which is in the CaSR, GSH activate the receptor directly the calcium-induced The of GSH were to reported for amino GSH appears to be in the high to the amino acid and the calcium used in the assay (5Conigrave A.D. Quinn S.J. Brown E.M. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4814-4819Crossref PubMed Scopus (407) Google Scholar, A.D. Mun H.C. Delbridge L. Quinn S.J. Wilkinson M. Brown E.M. J. Biol. Chem. 2004; 279: 38151-38159Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), the of GSH on the rat CaSR are in the Our that GSH also within the extracellular domain of the CaSR. The of C. C. C. H. E. D. M. J. Biol. Chem. 2005; 280: Full Text Full Text PDF PubMed Scopus Google that the calcium binding site in the CaSR is to and in to the amino acid binding site in the extracellular domain of the receptor. that amino GSH may act in ligands to of the extracellular domain and receptor the of also potentiated the CaSR, albeit the of to within the amino acid binding pocket of the CaSR the large size of the to binding at this site. However, the docking analysis that the putative amino acid pocket in the CaSR is large to accommodate the are the potential of GSH on Family C G-protein-coupled The 5.24 chemosensory receptor is expressed in the and of the fish and is thought to play a role in feeding and (1Speca D.J. Lin D.M. Sorensen P.W. Isacoff E.Y. Ngai J. Dittman A.H. Neuron. 1999; 23: 487-498Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar). Our suggest that the 5.24 receptor may also be used by fish to GSH the or In such as several of GSH a for feeding J. PubMed Scopus Google Scholar, K. A Mol. PubMed Scopus Google Scholar, P. C. A. P. C. A. J. Neurosci. 2004; PubMed Scopus Google Scholar). that the homolog of the fish 5.24 receptor may this In and the CaSR appears to play a role as a J. M. Quinn S. H. M. M. Bai M. N. Brown E.M. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: PubMed Scopus Google Scholar), in a role for this receptor is the regulation of parathyroid hormone The CaSR-mediated suppression of parathyroid hormone the for the a allosteric modulator of the CaSR for of N. J. Pharmacol. Sci. 2005; 97: PubMed Scopus Google Scholar). A is GSH could in modulate CaSR activity in as demonstrated by the that amino acids CaSR activity in human parathyroid cells (8Conigrave A.D. Mun H.C. Delbridge L. Quinn S.J. Wilkinson M. Brown E.M. J. Biol. Chem. 2004; 279: 38151-38159Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). In contrast to the high intracellular levels of GSH in mammalian cells A. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, Free Biol. 1999; PubMed Scopus Google Scholar), the extracellular of GSH in most tissues and in are in the of A. PubMed Scopus Google Scholar, Free Biol. 1999; PubMed Scopus Google Scholar). Our suggest that the of GSH on the CaSR is within the that could affect the regulation of CaSR-mediated responses in cells and Although of the for GSH at the CaSR is in the that the site could be in a of this These include the that were using the expressed receptor and the of may be in and that the extracellular GSH in tissues the putative endogenous levels of some are or the for receptors glutamate and the mGluR3 and of In addition to the parathyroid gland and the the CaSR is also expressed in the gastrointestinal tract where has been suggested to play a role as a S. J. Cell 2004; PubMed Scopus Google Scholar, D. D. 2005; PubMed Scopus Google Scholar). the cells the tract are to of amino acids and peptides such that GSH also be an in CaSR responses in this that in addition to the of GSH in the to modulation of intracellular and the of have also been of a GSH binding site in the brain K. Y. Res. PubMed Scopus Google Scholar, K. Y. C.A. J. Neurochem. 1999; PubMed Scopus Google Scholar, C.A. A. P. 2000; PubMed Scopus Google Scholar). Although neither the nor the of this binding site or potential receptor are are several the [3H]GSH binding site in brain and the These include the that the GSH binding site and the CaSR are expressed in and in the mammalian and the levels in several of the brain such as the and S. Brown E.M. Chattopadhyay N. Cell 2004; PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), are to and GSH binding to brain is enhanced in the presence of K. Y. C.A. J. Neurochem. 1999; PubMed Scopus Google Scholar). However, of the the of GSH reported on the CaSR and the GSH binding site or receptor J. S. J. and S. H. for CaSR, mGluR, and 5.24 and B. for the and on the also P. J. and B. for on and for on the

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