vomeronasal type-2 pheromone receptors, member of the class C family of seven-transmembrane G protein-coupled receptors; This group represents vomeronasal type-2 pheromone receptors (V2Rs). Members of the V2R family of vomeronasal GPCRs are involved in detecting protein pheromones for social and sexual cues between the same species. V2Rs and G-alpha(o) protein are coexpressed in the basal layer of the vomeronasal organ (VNO), which is the sensory organ of the accessory olfactory system present in amphibians, reptiles, and non-primate mammals such as mice and rodents, but it is non-functional or absent in humans, apes, and monkeys. On the other hand, members of the V1R receptor family and G-alpha(i2) protein are coexpressed in the apical neurons of the VNO. Activation of V1R or V2R causes activation of phospholipase pathway, producing the second messengers diacylglycerol (DAG) and IP3. However, in contrast to V1Rs, V2Rs contain the long N-terminal extracellular domain, which is believed to bind pheromones.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTV 585
Cdd:cd15283     1 PLGIALTVLSLLGSVLTAAVLVVFIKHRDTPIVKANNSELSYLLLLSLKLCFLCSLLFIGQPSTWTCMLRQTAFGISFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 586 AISTVLAKTITVVMAFKISTPGNRMKGMLTSGAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSEPGKTIVICNKGSI 665
Cdd:cd15283    81 CISCILAKTIVVVAAFKATRPGSNIMKWFGPGQQRAIIFICTLVQVVICAIWLATSPPFPDKNMHSEHGKIILECNEGSV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 666 FAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGLLG 745
Cdd:cd15283   161 VAFYCVLGYIGLLALVSFLLAFLARKLPDNFNEAKFITFSMLVFCAVWVAFVPAYISSPGKYMVAVEIFAILASSAGLLG 240

                         250
                  ....*....|..
gi 1958677300 746 CIFVPKCYVILV 757
Cdd:cd15283   241 CIFAPKCYIILL 252

Nine Cysteines Domain of family 3 GPCR; This conserved sequence contains several highly-conserved Cys residues that are predicted to form disulphide bridges. It is predicted to lie outside the cell membrane, tethered to the pfam00003 in several receptor proteins.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1958677300 433 PTSMCSVACIAGFRKIHQKQVTHCCFDCAHCPENEVSNeTDMEQCVRCPDDKYA 486
Cdd:pfam07562   1 PSSVCSESCPPGQRKSQQGGAPVCCWDCVPCPEGEISN-TDSDTCKKCPEGQWP 53

vomeronasal type-2 pheromone receptors, member of the class C family of seven-transmembrane G protein-coupled receptors; This group represents vomeronasal type-2 pheromone receptors (V2Rs). Members of the V2R family of vomeronasal GPCRs are involved in detecting protein pheromones for social and sexual cues between the same species. V2Rs and G-alpha(o) protein are coexpressed in the basal layer of the vomeronasal organ (VNO), which is the sensory organ of the accessory olfactory system present in amphibians, reptiles, and non-primate mammals such as mice and rodents, but it is non-functional or absent in humans, apes, and monkeys. On the other hand, members of the V1R receptor family and G-alpha(i2) protein are coexpressed in the apical neurons of the VNO. Activation of V1R or V2R causes activation of phospholipase pathway, producing the second messengers diacylglycerol (DAG) and IP3. However, in contrast to V1Rs, V2Rs contain the long N-terminal extracellular domain, which is believed to bind pheromones.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTV 585
Cdd:cd15283     1 PLGIALTVLSLLGSVLTAAVLVVFIKHRDTPIVKANNSELSYLLLLSLKLCFLCSLLFIGQPSTWTCMLRQTAFGISFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 586 AISTVLAKTITVVMAFKISTPGNRMKGMLTSGAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSEPGKTIVICNKGSI 665
Cdd:cd15283    81 CISCILAKTIVVVAAFKATRPGSNIMKWFGPGQQRAIIFICTLVQVVICAIWLATSPPFPDKNMHSEHGKIILECNEGSV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 666 FAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGLLG 745
Cdd:cd15283   161 VAFYCVLGYIGLLALVSFLLAFLARKLPDNFNEAKFITFSMLVFCAVWVAFVPAYISSPGKYMVAVEIFAILASSAGLLG 240

                         250
                  ....*....|..
gi 1958677300 746 CIFVPKCYVILV 757
Cdd:cd15283   241 CIFAPKCYIILL 252

7 transmembrane sweet-taste receptor of 3 GCPR; This is a domain of seven transmembrane regions that forms the C-terminus of some subclass 3 G-coupled-protein receptors. It is often associated with a downstream cysteine-rich linker domain, NCD3G pfam07562, which is the human sweet-taste receptor, and the N-terminal domain, ANF_receptor pfam01094. The seven TM regions assemble in such a way as to produce a docking pocket into which such molecules as cyclamate and lactisole have been found to bind and consequently confer the taste of sweetness.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 501 LAYEDPLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNhITCILQQTTFG 580
Cdd:pfam00003   1 LDLSAPWGIVLEALAALGILLTLVLLVVFLLHRKTPIVKASNRSLSFLLLLGLLLLFLLAFLFIGKPT-VTCALRRFLFG 79

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 581 VFFTVAISTVLAKTITVVMAFKISTPGNRMKGMLtsgapnLVIPICTLIQLVLCGIWLGTsPPFIDRDIQSEpGKTIVIC 660
Cdd:pfam00003  80 VGFTLCFSCLLAKTFRLVLIFRRRKPGPRGWQLL------LLALGLLLVQVIILTEWLID-PPFPEKDNLSE-GKIILEC 151

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 661 NKGSIFAF-HFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVY-HSTKGKVM---VVVEVFS 735
Cdd:pfam00003 152 EGSTSIAFlDFVLAYVGLLLLAGFLLAFKTRKLPDNFNEAKFITFSMLLSVLIWVAFIPMYlYGNKGKGTwdpVALAIFA 231

                         250
                  ....*....|....*.
gi 1958677300 736 ILASSAGLLGCIFVPK 751
Cdd:pfam00003 232 ILASGWVLLGLYFIPK 247

Nine Cysteines Domain of family 3 GPCR; This conserved sequence contains several highly-conserved Cys residues that are predicted to form disulphide bridges. It is predicted to lie outside the cell membrane, tethered to the pfam00003 in several receptor proteins.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1958677300 433 PTSMCSVACIAGFRKIHQKQVTHCCFDCAHCPENEVSNeTDMEQCVRCPDDKYA 486
Cdd:pfam07562   1 PSSVCSESCPPGQRKSQQGGAPVCCWDCVPCPEGEISN-TDSDTCKKCPEGQWP 53

vomeronasal type-2 pheromone receptors, member of the class C family of seven-transmembrane G protein-coupled receptors; This group represents vomeronasal type-2 pheromone receptors (V2Rs). Members of the V2R family of vomeronasal GPCRs are involved in detecting protein pheromones for social and sexual cues between the same species. V2Rs and G-alpha(o) protein are coexpressed in the basal layer of the vomeronasal organ (VNO), which is the sensory organ of the accessory olfactory system present in amphibians, reptiles, and non-primate mammals such as mice and rodents, but it is non-functional or absent in humans, apes, and monkeys. On the other hand, members of the V1R receptor family and G-alpha(i2) protein are coexpressed in the apical neurons of the VNO. Activation of V1R or V2R causes activation of phospholipase pathway, producing the second messengers diacylglycerol (DAG) and IP3. However, in contrast to V1Rs, V2Rs contain the long N-terminal extracellular domain, which is believed to bind pheromones.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTV 585
Cdd:cd15283     1 PLGIALTVLSLLGSVLTAAVLVVFIKHRDTPIVKANNSELSYLLLLSLKLCFLCSLLFIGQPSTWTCMLRQTAFGISFVL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 586 AISTVLAKTITVVMAFKISTPGNRMKGMLTSGAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSEPGKTIVICNKGSI 665
Cdd:cd15283    81 CISCILAKTIVVVAAFKATRPGSNIMKWFGPGQQRAIIFICTLVQVVICAIWLATSPPFPDKNMHSEHGKIILECNEGSV 160

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 666 FAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGLLG 745
Cdd:cd15283   161 VAFYCVLGYIGLLALVSFLLAFLARKLPDNFNEAKFITFSMLVFCAVWVAFVPAYISSPGKYMVAVEIFAILASSAGLLG 240

                         250
                  ....*....|..
gi 1958677300 746 CIFVPKCYVILV 757
Cdd:cd15283   241 CIFAPKCYIILL 252

vomeronasal type-2 pheromone receptors, amino acid-sensing receptors and closely related proteins; member of the class C family of seven-transmembrane G protein-coupled receptors; This group is composed of vomeronasal type-2 pheromone receptors (V2Rs), a subgroup of broad-spectrum amino-acid sensing receptors including calcium-sensing receptor (CaSR) and GPRC6A, as well as their closely related proteins. Members of the V2R family of vomeronasal GPCRs are involved in detecting protein pheromones for social and sexual cues between the same species. V2Rs and G-alpha(o) protein are co-expressed in the basal layer of the vomeronasal organ (VNO), which is the sensory organ of the accessory olfactory system present in amphibians, reptiles, and non-primate mammals such as mice and rodents, but it is non-functional or absent in humans, apes, and monkeys. On the other hand, members of the V1R receptor family and G-alpha(i2) protein are co-expressed in the apical neurons of the VNO. Activation of V1R or V2R causes activation of phospholipase pathway, producing the second messengers diacylglycerol (DAG) and IP3. However, in contrast to V1Rs, V2Rs contain the long N-terminal extracellular domain, which is believed to bind pheromones. CaSR is a widely expressed GPCR that is involved in sensing small changes in extracellular levels of calcium ion to maintain a constant level of the extracellular calcium via modulating the synthesis and secretion of calcium regulating hormones, such as parathyroid hormone (PTH), in order to regulate Ca(2+)transport into or out of the extracellular fluid via kidney, intestine, and/or bone. For instance, when Ca2+ is high, CaSR downregulates PTH synthesis and secretion, leading to an increase in renal Ca2+ excretion, a decrease in intestinal Ca2+ absorption, and a reduction in release of skeletal Ca2+. GRPC6A (GPCR, class C, group 6, subtype A) is a widely expressed amino acid-sensing GPCR that is most closely related to CaSR. GPRC6A is most potently activated by the basic amino acids L-arginine, L-lysine, and L-ornithine and less potently by small aliphatic amino acids. Moreover, the receptor can be either activated or modulated by divalent cations such as Ca2+. GPRC6A is expressed in the testis, but not the ovary and specifically also binds to the osteoblast-derived hormone osteocalcin (OCN), which regulates testosterone production by the testis and male fertility independently of the hypothalamic-pituitary axis. Furthermore, GPRC6A knockout studies suggest that GRPC6A is involved in regulation of bone metabolism, male reproduction, energy homeostasis, glucose metabolism, and in activation of inflammation response, as well as prostate cancer growth and progression, among others.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTV 585
Cdd:cd15044     1 PLGILLVILSILGIIFVLVVGGVFVRYRNTPIVKANNRELSYLILLSLFLCFSSSLFFIGEPQDWTCKLRQTMFGVSFTL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 586 AISTVLAKTITVVMAFKISTPGNRMKGMLTSgAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSEPGKTIVICNKGSI 665
Cdd:cd15044    81 CISCILTKTLKVLLAFSADKPLTQKFLMCLY-LPILIVFTCTGIQVVICTVWLIFAPPTVEVNVSPLPRVIILECNEGSI 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 666 FAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGLLG 745
Cdd:cd15044   160 LAFGTMLGYIAFLAFLCFLFAFKARKLPDNYNEAKFITFGMLVFFIVWISFVPAYLSTKGKFVVAVEIIAILASSYGLLG 239

                         250
                  ....*....|.
gi 1958677300 746 CIFVPKCYVIL 756
Cdd:cd15044   240 CIFLPKCYVIL 250

vomeronasal type-2 receptor-like proteins, member of the class C family of seven-transmembrane G protein-coupled receptors; This group represents vomeronasal type-2 receptor-like proteins that are closely related to the V2R family of vomeronasal GPCRs. Members of the V2R family of vomeronasal GPCRs are involved in detecting protein pheromones for social and sexual cues between the same species. V2Rs and G-alpha(o) protein are coexpressed in the basal layer of the vomeronasal organ (VNO), which is the sensory organ of the accessory olfactory system present in amphibians, reptiles, and non-primate mammals such as mice and rodents, but it is non-functional or absent in humans, apes, and monkeys. On the other hand, members of the V1R receptor family and G-alpha(i2) protein are co-expressed in the apical neurons of the VNO. Activation of V1R or V2R causes activation of phospholipase pathway, generating the secondary messengers diacylglycerol (DAG) and IP3. However, in contrast to V1Rs, V2Rs contain the long N-terminal extracellular domain, which is believed to bind pheromones. Human V2R1-like protein, also known as putative calcium-sensing receptor-like 1 (CASRL1), is not included here because it is a nonfunctional pseudogene.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTV 585
Cdd:cd15280     1 ALGITLIALSIFGALVVLAVTVVYIMHRHTPLVKANDRELSFLIQMSLVITFLTSILFIGKPENWSCMARQITLALGFSL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 586 AISTVLAKTITVVMAFKISTPGNRMKGMlTSGAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSEPGKTIVICNKGSI 665
Cdd:cd15280    81 CLSSILGKTISLFLRYRASKSETRLDSM-HPIYQKIIVLICVLIEVGICTAYLILEPPRMYKNTEVQNVKIIFECNEGSI 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 666 FAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGLLG 745
Cdd:cd15280   160 EFLCSIFGFDVFLALLCFLTAFVARKLPDNFNEGKFITFGMLVFFIVWISFVPAYLSTRGKFKVAVEIFAILASSFGLLG 239

                         250
                  ....*....|...
gi 1958677300 746 CIFVPKCYVILVR 758
Cdd:cd15280   240 CIFVPKCYIILLK 252

metabotropic glutamate receptor-like class C family of seven-transmembrane G protein-coupled receptors superfamily; The class C GPCRs consist of glutamate receptors (mGluR1-8), the extracellular calcium-sensing receptors (caSR), the gamma-amino-butyric acid type B receptors (GABA-B), the vomeronasal type-2 pheromone receptors (V2R), the type 1 taste receptors (TAS1R), and the promiscuous L-alpha-amino acid receptor (GPRC6A), as well as several orphan receptors. Structurally, these receptors are typically composed of a large extracellular domain containing a Venus flytrap module which possesses the orthosteric agonist-binding site, a cysteine-rich domain (CRD) with the exception of GABA-B receptors, and the seven-transmembrane domains responsible for G protein activation. Moreover, the Venus flytrap module shows high structural homology with bacterial periplasmic amino acid-binding proteins, which serve as primary receptors in transport of a variety of soluble substrates such as amino acids and polysaccharides, among many others. The class C GPCRs exist as either homo- or heterodimers, which are essential for their function. The GABA-B1 and GABA-B2 receptors form a heterodimer via interactions between the N-terminal Venus flytrap modules and the C-terminal coiled-coiled domains. On the other hand, heterodimeric CaSRs and Tas1Rs and homodimeric mGluRs utilize Venus flytrap interactions and intermolecular disulphide bonds between cysteine residues located in the cysteine-rich domain (CRD), which can also acts as a molecular link to mediate the signal between the Venus flytrap and the 7TMs. Furthermore, members of the class C GPCRs bind a variety of endogenous ligands, ranging from amino acids, ions, to pheromones and sugar molecules, and play important roles in many physiological processes such as synaptic transmission, calcium homeostasis, and the sensation of sweet and umami tastes.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTV 585
Cdd:cd13953     1 PLAIVLLVLAALGLLLTIFIWVVFIRYRNTPVVKASNRELSYLLLFGILLCFLLAFLFLLPPSDVLCGLRRFLFGLSFTL 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 586 AISTVLAKTITVVMAFKISTPGNRMKGMLTSGAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSEpGKTIVICNKGSI 665
Cdd:cd13953    81 VFSTLLVKTNRIYRIFKSGLRSSLRPKLLSNKSQLLLVLFLLLVQVAILIVWLILDPPKVEKVIDSD-NKVVELCCSTGN 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 666 FAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGLLG 745
Cdd:cd13953   160 IGLILSLVYNILLLLICTYLAFKTRKLPDNFNEARYIGFSSLLSLVIWIAFIPTYFTTSGPYRDAILSFGLLLNATVLLL 239

                         250
                  ....*....|.
gi 1958677300 746 CIFVPKCYVIL 756
Cdd:cd13953   240 CLFLPKIYIIL 250

type 1 taste receptor subtype 3, member of the class C of seven-transmembrane G protein-coupled receptors; This group represents TAS1R3, which is a member of the type I taste receptor (TAS1R) family that belongs to the class C of G protein-coupled receptors. The functional TAS1Rs are obligatory heterodimers built from three known members, TAS1R1-3. TAS1R1 combines with TAS1R3 to form an umami taste receptor, which is responsible for the perception of savory taste, such as the food additive mono-sodium glutamate (MSG); whereas the combination of TAS1R2-TAS1R3 forms a sweet-taste receptor for sugars and D-amino acids. On the other hand, the type II taste receptors (TAS2Rs), which belong to the class A family of GPCRs, recognize bitter tasting compounds. In the case of sweet, for example, the TAS1R2-TAS1R3 heterodimer activates phospholipase C (PLC) via alpha-gustducin, a heterodimeric G protein that is involved in perception of sweet and bitter tastes. This activation leads to generation of inositol (1, 4, 5)-trisphosphate (IP3) and diacylglycerol (DAG), and consequently increases intracellular Ca2+ mobilization and activates a cation channel, TRPM5. In contrast to the TAS1R2-TAS1R3 heterodimer, TAS1R3 alone could activate adenylate cyclase leading to cAMP formation in the absence of alpha-gustducin. Each TAS1R contains a large extracellular Venus flytrap-like domain in the N-terminus, cysteine-rich domain (CRD) and seven-transmembrane (7TM) domain, which are characteristics of the class C GPCRs. The Venus flytrap-like domain shares strong sequence homology to bacterial periplasmic binding proteins and possess the orthosteric amino acid and calcium binding sites for members of the class C, including CaSR, GABA-B1, GPRC6A, mGlu, and TAS1R receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 507 LGMALGCTALCFSTLTVLILFtfLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTVA 586
Cdd:cd15290     4 LGLLLLGVLLLVLQCSVGVLF--LKHRGTPLVQASGGPLSIFALLSLMGACLSLLLFLGQPSDVVCRLQQPLNALFLTVC 81

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 587 ISTVLAKT--ITVVMAFKISTPGnrMKGMLTSGAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSE-PGKTIVICNKG 663
Cdd:cd15290    82 LSTILSISlqIFLVTEFPKCAAS--HLHWLRGPGSWLVVLICCLVQAGLCGWYVQDGPSLSEYDAKMTlFVEVFLRCPVE 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 664 SIFAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGL 743
Cdd:cd15290   160 PWLGFGLMHGFNGALALISFMCTFMAQKPLKQYNLARDITFSTLIYCVTWVIFIPIYAGLQVKLRSIAQVGFILLSNLGL 239

                         250
                  ....*....|...
gi 1958677300 744 LGCIFVPKCYVIL 756
Cdd:cd15290   240 LAAYYLPKCYLLL 252

type 1 taste receptor subtype 1, member of the class C of seven-transmembrane G protein-coupled receptors; This group represents TAS1R1, which is a member of the type I taste receptor (TAS1R) family that belongs to the class C of G protein-coupled receptors. The functional TAS1Rs are obligatory heterodimers built from three known members, TAS1R1-3. TAS1R1 combines with TAS1R3 to form an umami taste receptor, which is responsible for the perception of savory taste, such as the food additive mono-sodium glutamate (MSG); whereas the combination of TAS1R2-TAS1R3 forms a sweet-taste receptor for sugars and D-amino acids. On the other hand, the type II taste receptors (TAS2Rs), which belong to the class A family of GPCRs, recognize bitter tasting compounds. In the case of sweet, for example, the TAS1R2-TAS1R3 heterodimer activates phospholipase C (PLC) via alpha-gustducin, a heterodimeric G protein that is involved in perception of sweet and bitter tastes. This activation leads to generation of inositol (1, 4, 5)-trisphosphate (IP3) and diacylglycerol (DAG), and consequently increases intracellular Ca2+ mobilization and activates a cation channel, TRPM5. In contrast to the TAS1R2-TAS1R3 heterodimer, TAS1R3 alone could activate adenylate cyclase leading to cAMP formation in the absence of alpha-gustducin. Each TAS1R contains a large extracellular Venus flytrap-like domain in the N-terminus, cysteine-rich domain (CRD) and seven-transmembrane (7TM) domain, which are characteristics of the class C GPCRs. The Venus flytrap-like domain shares strong sequence homology to bacterial periplasmic binding proteins and possess the orthosteric amino acid and calcium binding sites for members of the class C, including CaSR, GABA-B1, GPRC6A, mGlu, and TAS1R receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALgctaLCFSTLTVLIL----FTFLKYKDTPIVKANNCLLsyillislifCFL---------CSLL-FIGHPNHIT 571
Cdd:cd15289     1 PVSWAL----LTALTLLLLLLagtaLLFALNLTTPVVKSAGGRT----------CFLmlgslaaasCSLYcHFGEPTWLA 66

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 572 CILQQTTFGVFFTVAISTVLAKTITVVMAFKISTPGNRM-KGMLTSGAPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQ 650
Cdd:cd15289    67 CLLKQPLFSLSFTVCLSCIAVRSFQIVCIFKLASKLPRFyETWAKNHGPELFILISSAVQLLISLLWLVLNPPVPTKDYD 146

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 651 SEPGKTIVICNKGSIFAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVV 730
Cdd:cd15289   147 RYPDLIVLECSQTLSVGSFLELLYNCLLSISCFVFSYMGKDLPANYNEAKCITFSLLIYFISWISFFTTYSIYRGKYLMA 226

                         250       260
                  ....*....|....*....|....*.
gi 1958677300 731 VEVFSILASSAGLLGCIFVPKCYVIL 756
Cdd:cd15289   227 INVLAILSSLLGIFGGYFLPKVYIIL 252

type 1 taste receptors, member of the class C of seven-transmembrane G protein-coupled receptors; This subfamily represents the type I taste receptors (TAS1Rs) that belongs to the class C family of G protein-coupled receptors. The functional TAS1Rs are obligatory heterodimers built from three known members, TAS1R1-3. TAS1R1 combines with TAS1R3 to form an umami taste receptor, which is responsible for the perception of savory taste, such as the food additive mono-sodium glutamate (MSG); whereas the combination of TAS1R2-TAS1R3 forms a sweet-taste receptor for sugars and D-amino acids. On the other hand, the type II taste receptors (TAS2Rs), which belong to the class A family of GPCRs, recognize bitter tasting compounds. In the case of sweet, for example, the TAS1R2-TAS1R3 heterodimer activates phospholipase C (PLC) via alpha-gustducin, a heterodimeric G protein that is involved in perception of sweet and bitter tastes. This activation leads to generation of inositol (1, 4, 5)-trisphosphate (IP3) and diacylglycerol (DAG), and consequently increases intracellular Ca2+ mobilization and activates a cation channel, TRPM5. In contrast to the TAS1R2-TAS1R3 heterodimer, TAS1R3 alone could activate adenylate cyclase leading to cAMP formation in the absence of alpha-gustducin. Each TAS1R contains a large extracellular Venus flytrap-like domain in the N-terminus, cysteine-rich domain (CRD) and seven-transmembrane (7TM) domain, which are characteristics of the class C GPCRs. The Venus flytrap-like domain shares strong sequence homology to bacterial periplasmic binding proteins and possess the orthosteric amino acid and calcium binding sites for members of the class C, including CaSR, GABA-B1, GPRC6A, mGlu, and TAS1R receptors.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 506 PLGMALGCTALCFSTLTVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTV 585
Cdd:cd15046     1 APTVAVLLLAALGLLSTLAILVIFWRNFNTPVVRSAGGPMCFLMLTLLLVAYMSVPVYFGPPKVSTCLLRQALFPLCFTV 80

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 586 AISTVLAKTITVVMAFKIST--PGNRMKGMLTSGaPNLVIPICTLIQLVLCGIWLGTSPPFIDRDIQSEPGKTIVICNKG 663
Cdd:cd15046    81 CLACIAVRSFQIVCIFKMASrfPRAYSYWVKYHG-PYVSIAFITVLKMVIVVIGMLATPPSPTTDTDPDPKITIVSCNPN 159

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 664 SIFAFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAGL 743
Cdd:cd15046   160 YRNSSLFNTSLDLLLSVVCFSFSYMGKDLPTNYNEAKFITFSLTFYFTSWISFCTFMLAYSGVLVTIVDLLATLLSLLAF 239

                         250
                  ....*....|...
gi 1958677300 744 LGCIFVPKCYVIL 756
Cdd:cd15046   240 SLGYFLPKCYIIL 252

metabotropic glutamate receptors in group 1, member of the class C family of seven-transmembrane G protein-coupled receptors; Group 1 mGluRs includes mGluR1 and mGluR5, as well as their closely related invertebrate receptors. They are homodimeric class C G-protein coupled receptors which are activated by glutamate, the major excitatory neurotransmitter of the CNS. mGluRs are involved in regulating neuronal excitability and synaptic transmission via intracellular activation of second messenger signaling pathways. While the ionotropic glutamate receptor subtypes (AMPA, NMDA, and kainite) mediate fast excitatory postsynaptic transmission, mGluRs are known to mediate slower excitatory postsynaptic responses and to be involved in synaptic plasticity in the mammalian brain. In addition to seven-transmembrane helices, the class C GPCRs are characterized by a large N-terminal extracellular Venus flytrap-like domain, which is composed of two adjacent lobes separated by a cleft which binds an endogenous ligand. Moreover, they exist as either homo- or heterodimers, which are essential for their function. For instance, mGluRs form homodimers via interactions between the N-terminal Venus flytrap domains and the intermolecular disulphide bonds between cysteine residues located in the cysteine-rich domain (CRD). At least eight different subtypes of metabotropic receptors (mGluR1-8) have been identified and further classified into three groups based on their sequence homology, pharmacological properties, and signaling pathways. Group 1 (mGluR1 and mGluR5) receptors are predominantly located postsynaptically on neurons and are involved in long-term synaptic plasticity in the brain, including long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum. They are coupled to G(q/11) proteins, thereby activating phospholipase C to generate inositol-1,4,5-triphosphate (IP3) and diacyglycerol (DAG), which in turn lead to Ca2+ release and protein kinase C activation, respectively. Group 1 mGluR expression is shown to be strongly upregulated in animal models of epilepsy, brain injury, inflammatory, and neuropathic pain, as well as in patients with amyotrophic lateral sclerosis or multiple sclerosis. Group 2 (mGluR2 and mGluR3) and 3 (mGluR4, mGluR6, mGluR7, and mGluR8) receptors are predominantly localized presynaptically in the active region of neurotransmitter release. They are coupled to G(i/o) proteins, which leads to inhibition of adenylate cyclase activity and cAMP formation, and consequently to a decrease in protein kinase A (PKA) activity. Ultimately, activation of these receptors leads to inhibition of neurotransmitter release such as glutamate and GABA via inhibition of Ca2+ channels and activation of K+ channels. Furthermore, while activation of Group 1 mGluRs increases NMDA (N-methyl-D-aspartate) receptor activity and risk of neurotoxicity, Group 2 and 3 mGluRs decrease NMDA receptor activity and prevent neurotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 514 TALCFSTL----TVLILFTFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTVAIST 589
Cdd:cd15285     5 VAMVFACVgilaTLFVTVVFIRHNDTPVVKASTRELSYIILAGILLCYASTFALLAKPSTISCYLQRILPGLSFAMIYAA 84

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 590 VLAKT--ITVVMAFKISTPGNRmKGMLTSGAPNLVIP-ICTLIQLVLCGIWLGTSPPFIDRDIQSePGKTIVICNKgSIF 666
Cdd:cd15285    85 LVTKTnrIARILAGSKKKILTR-KPRFMSASAQVVITgILISVEVAIIVVMLILEPPDATLDYPT-PKRVRLICNT-STL 161

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 667 AFHFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVveVFSILASSAGLLGC 746
Cdd:cd15285   162 GFVVPLGFDFLLILLCTLYAFKTRNLPENFNEAKFIGFTMYTTCVIWLAFLPIYFGSDNKEITL--CFSVSLSATVALVF 239

                         250
                  ....*....|
gi 1958677300 747 IFVPKCYVIL 756
Cdd:cd15285   240 LFFPKVYIIL 249

metabotropic glutamate receptor 2 in group 2, member of the class C family of seven-transmembrane G protein-coupled receptors; The metabotropic glutamate receptors (mGluRs) in group 2 include mGluR 2 and 3. They are homodimeric class C G-protein coupled receptors which are activated by glutamate, the major excitatory neurotransmitter of the CNS. mGluRs are involved in regulating neuronal excitability and synaptic transmission via intracellular activation of second messenger signaling pathways. While the ionotropic glutamate receptor subtypes (AMPA, NMDA, and kainite) mediate fast excitatory postsynaptic transmission, mGluRs are known to mediate slower excitatory postsynaptic responses and to be involved in synaptic plasticity in the mammalian brain. In addition to seven-transmembrane helices, the class C GPCRs are characterized by a large N-terminal extracellular Venus flytrap-like domain, which is composed of two adjacent lobes separated by a cleft which binds an endogenous ligand. Moreover, they exist as either homo- or heterodimers, which are essential for their function. For instance, mGluRs form homodimers via interactions between the N-terminal Venus flytrap domains and the intermolecular disulphide bonds between cysteine residues located in the cysteine-rich domain (CRD). At least eight different subtypes of metabotropic receptors (mGluR1-8) have been identified and further classified into three groups based on their sequence homology, pharmacological properties, and signaling pathways. Group 1 (mGluR1 and mGluR5) receptors are predominantly located postsynaptically on neurons and are involved in long-term synaptic plasticity in the brain, including long-term potentiation (LTP) in the hippocampus and long-term depression (LTD) in the cerebellum. They are coupled to G(q/11) proteins, thereby activating phospholipase C to generate inositol-1,4,5-triphosphate (IP3) and diacyglycerol (DAG), which in turn lead to Ca2+ release and protein kinase C activation, respectively. Group 1 mGluR expression is shown to be strongly upregulated in animal models of epilepsy, brain injury, inflammatory, and neuropathic pain, as well as in patients with amyotrophic lateral sclerosis or multiple sclerosis. Group 2 (mGluR2 and mGluR3) and 3 (mGluR4, mGluR6, mGluR7, and mGluR8) receptors are predominantly localized presynaptically in the active region of neurotransmitter release. They are coupled to G(i/o) proteins, which leads to inhibition of adenylate cyclase activity and cAMP formation, and consequently to a decrease in protein kinase A (PKA) activity. Ultimately, activation of these receptors leads to inhibition of neurotransmitter release such as glutamate and GABA via inhibition of Ca2+ channels and activation of K+ channels. Furthermore, while activation of Group 1 mGluRs increases NMDA (N-methyl-D-aspartate) receptor activity and risk of neurotoxicity, Group 2 and 3 mGluRs decrease NMDA receptor activity and prevent neurotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 514 TALCFSTLTVLILF-TFLKYKDTPIVKANNCLLSYILLISLIFCFLCSLLFIGHPNHITCILQQTTFGVFFTVAISTVLA 592
Cdd:cd15447     8 TISCLGILSTLFVVgVFVKNNETPVVKASGRELCYILLLGVLLCYLMTFIFIAKPSTAVCTLRRLGLGTSFAVCYSALLT 87

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 593 KTITVVMAFKISTPGNRMKGMLTsgaPNLVIPICTLI---QLVLCGIWLGTSPPFIDRDIQSEPGKTIVI-CNKGSIfAF 668
Cdd:cd15447    88 KTNRIARIFSGAKDGAQRPRFIS---PASQVAICLALiscQLLVVLIWLLVEAPGTRKETAPERRYVVTLkCNSRDS-SM 163

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1958677300 669 HFTLGYLDSLTLMSFAVAFLARNLPDRFNEAKFLTFSMLVFCSVWITFLPVYHSTKGKVMVVVEVFSILASSAG--LLGC 746
Cdd:cd15447   164 LISLTYNVLLIILCTLYAFKTRKCPENFNEAKFIGFTMYTTCIIWLAFLPIFYVTSSDYRVQTTTMCISVSLSGsvVLGC 243

                         250
                  ....*....|
gi 1958677300 747 IFVPKCYVIL 756
Cdd:cd15447   244 LFAPKLHIIL 253