Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function
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Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function. / Jorgensen, Stine; Have, Christian Theil; Underwood, Christina Rye; Johansen, Lars Dan; Wellendorph, Petrine; Gjesing, Anette Prior; Jorgensen, Christinna V.; Quan, Shi; Rui, Gao; Inoue, Asuka; Linneberg, Allan; Grarup, Niels; Jun, Wang; Pedersen, Oluf; Hansen, Torben; Bräuner-Osborne, Hans.
In: The Journal of Biological Chemistry, Vol. 292, No. 4, 2017, p. 1524-1534.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function
AU - Jorgensen, Stine
AU - Have, Christian Theil
AU - Underwood, Christina Rye
AU - Johansen, Lars Dan
AU - Wellendorph, Petrine
AU - Gjesing, Anette Prior
AU - Jorgensen, Christinna V.
AU - Quan, Shi
AU - Rui, Gao
AU - Inoue, Asuka
AU - Linneberg, Allan
AU - Grarup, Niels
AU - Jun, Wang
AU - Pedersen, Oluf
AU - Hansen, Torben
AU - Bräuner-Osborne, Hans
PY - 2017
Y1 - 2017
N2 - GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional. By analyses of chimeric human/mouse and human/bonobo receptors, bonobo receptor mutants, and the single nucleotide polymorphism database at NCBI, we identify an insertion/deletion variation in the third intracellular loop responsible for the intracellular retention and lack of function of the human ortholog. Genetic analyses of the 1000 genome database and the Inter99 cohort of 6,000 Danes establish the distribution of genotypes among ethnic groups, showing that the cell surface-expressed and functional variant is much more prevalent in the African population than in European and Asian populations and that this variant is partly linked with a stop codon early in the receptor sequence (rs6907580, amino acid position 57). In conclusion, our data solve a more than decade-old question of why the cloned human GPRC6A receptor is not cell surface-expressed and functional and provide a genetic framework to study human phenotypic traits in large genome sequencing projects linked with physiological measurement and biomarkers.[on SciFinder (R)]
AB - GPRC6A is a G protein-coupled receptor activated by l-amino acids, which, based on analyses of knock-out mice, has been suggested to have physiological functions in metabolism and testicular function. The human ortholog is, however, mostly retained intracellularly in contrast to the cell surface-expressed murine and goldfish orthologs. The latter orthologs are Gq-coupled and lead to intracellular accumulation of inositol phosphates and calcium release. In the present study we cloned the bonobo chimpanzee GPRC6A receptor, which is 99% identical to the human receptor, and show that it is cell surface-expressed and functional. By analyses of chimeric human/mouse and human/bonobo receptors, bonobo receptor mutants, and the single nucleotide polymorphism database at NCBI, we identify an insertion/deletion variation in the third intracellular loop responsible for the intracellular retention and lack of function of the human ortholog. Genetic analyses of the 1000 genome database and the Inter99 cohort of 6,000 Danes establish the distribution of genotypes among ethnic groups, showing that the cell surface-expressed and functional variant is much more prevalent in the African population than in European and Asian populations and that this variant is partly linked with a stop codon early in the receptor sequence (rs6907580, amino acid position 57). In conclusion, our data solve a more than decade-old question of why the cloned human GPRC6A receptor is not cell surface-expressed and functional and provide a genetic framework to study human phenotypic traits in large genome sequencing projects linked with physiological measurement and biomarkers.[on SciFinder (R)]
KW - 7-helix receptor
KW - g protein-coupled receptor (gpcr)
KW - gprc6a receptor
KW - cell surface receptor
KW - human genetics
KW - molecular pharmacology
KW - third intracellular loop
U2 - 10.1074/jbc.M116.756577
DO - 10.1074/jbc.M116.756577
M3 - Journal article
C2 - 27986810
VL - 292
SP - 1524
EP - 1534
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 4
ER -
ID: 174465386