Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function

Stine Jorgensen; Christian Theil Have; Christina Rye Underwood; Lars Dan Johansen; Petrine Wellendorph; Anette Prior Gjesing; Christinna V. Jorgensen; Shi Quan; Gao Rui; Asuka Inoue; Allan Linneberg; Niels Grarup; Wang Jun; Oluf Pedersen; Torben Hansen; Hans Bräuner-Osborne

doi:10.1074/jbc.m116.756577

Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function

Stine Jorgensen, Christian Theil Have, Christina Rye Underwood, Lars Dan Johansen, Petrine Wellendorph, Anette Prior Gjesing, Christinna V. Jorgensen, Shi Quan, Gao Rui, Asuka Inoue, Allan Linneberg, Niels Grarup, Wang Jun, Oluf Pedersen, Torben Hansen, Hans Bräuner-Osborne

Department of Clinical Medicine

16 Citations (Scopus)

Abstract

GPRC6A is a G protein-coupled receptor activated by Lamino 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 areGq-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.

Original language	English
Journal	The Journal of Biological Chemistry
Volume	292
Issue number	4
Pages (from-to)	1524-1534
Number of pages	11
ISSN	1083-351X
DOIs	https://doi.org/10.1074/jbc.m116.756577
Publication status	Published - 27 Jan 2017

Keywords

7-helix receptor
g protein-coupled receptor (gpcr)
gprc6a receptor
cell surface receptor
human genetics
molecular pharmacology
third intracellular loop

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Jorgensen, S., Have, C. T., Underwood, C. R., Johansen, L. D., Wellendorph, P., Gjesing, A. P., Jorgensen, C. V., Quan, S., Rui, G., Inoue, A., Linneberg, A., Grarup, N., Jun, W., Pedersen, O., Hansen, T., & Bräuner-Osborne, H. (2017). Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function. The Journal of Biological Chemistry, 292(4), 1524-1534. https://doi.org/10.1074/jbc.m116.756577

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 et al.
In: The Journal of Biological Chemistry, Vol. 292, No. 4, 27.01.2017, p. 1524-1534.

Research output: Contribution to journal › Journal article › Research › peer-review

Jorgensen, S, Have, CT, Underwood, CR, Johansen, LD, Wellendorph, P, Gjesing, AP, Jorgensen, CV, Quan, S, Rui, G, Inoue, A, Linneberg, A , Grarup, N, Jun, W, Pedersen, O , Hansen, T & Bräuner-Osborne, H 2017, 'Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function', The Journal of Biological Chemistry, vol. 292, no. 4, pp. 1524-1534. https://doi.org/10.1074/jbc.m116.756577

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title = "Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function",

abstract = "GPRC6A is a G protein-coupled receptor activated by Lamino 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 areGq-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.",

keywords = "7-helix receptor, g protein-coupled receptor (gpcr), gprc6a receptor, cell surface receptor, human genetics, molecular pharmacology, third intracellular loop",

author = "Stine Jorgensen and Have, {Christian Theil} and Underwood, {Christina Rye} and Johansen, {Lars Dan} and Petrine Wellendorph and Gjesing, {Anette Prior} and Jorgensen, {Christinna V.} and Shi Quan and Gao Rui and Asuka Inoue and Allan Linneberg and Niels Grarup and Wang Jun and Oluf Pedersen and Torben Hansen and Hans Br{\"a}uner-Osborne",

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doi = "10.1074/jbc.m116.756577",

language = "English",

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journal = "The Journal of Biological Chemistry",

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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 - 2017/1/27

Y1 - 2017/1/27

N2 - GPRC6A is a G protein-coupled receptor activated by Lamino 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 areGq-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.

AB - GPRC6A is a G protein-coupled receptor activated by Lamino 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 areGq-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.

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

SN - 1083-351X

VL - 292

SP - 1524

EP - 1534

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

IS - 4

ER -

Genetic Variations in the Human G Protein-coupled Receptor Class C, Group 6, Member A (GPRC6A) Control Cell Surface Expression and Function

Abstract

Keywords

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