Characterization of signalling and regulation of common calcitonin receptor splice variants and polymorphisms

Emma Dal Maso, Rasmus Just, Caroline Hick, Arthur Christopoulos, Patrick M. Sexton, Denise Wootten, Sebastian G.B. Furness

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is a therapeutic target for the treatment of hypercalcaemia of malignancy, Paget's disease and osteoporosis. In primates, the CTR is subject to alternative splicing, with a unique, primate-specific splice variant being preferentially expressed in reproductive organs, lung and kidney. In addition, humans possess a common non-synonymous single-nucleotide polymorphism (SNP) encoding a proline/leucine substitution in the C-terminal tail. In low power studies, the leucine polymorphism has been associated with increased risk of osteoporosis in East Asian populations and, independently, with increased risk of kidney stone disease in a central Asian population. The CTR is pleiotropically coupled, though the relative physiological importance of these pathways is poorly understood. Using both COS-7 and HEK293 cells recombinantly expressing human CTR, we have characterized both splice variant and polymorphism dependent response to CTs from several species in key signalling pathways and competition binding assays. These data indicate that the naturally occurring changes to the intracellular face of CTR alter ligand affinity and signalling, in a pathway and agonist dependent manner. These results further support the potential for these primate-specific CTR variants to engender different physiological responses. In addition, we report that the CTR exhibits constitutive internalization, independent of splice variant and polymorphism and this profile is unaltered by peptide binding.

Original languageEnglish
Pages (from-to)111-129
Number of pages19
JournalBiochemical Pharmacology
Volume148
DOIs
Publication statusPublished - 1 Feb 2018

Keywords

  • Calcitonin
  • Calcitonin receptor
  • G protein-coupled receptor
  • Polymorphism
  • Splice variant

Cite this

@article{20732c0b9be04bbaa7184febcf330b8a,
title = "Characterization of signalling and regulation of common calcitonin receptor splice variants and polymorphisms",
abstract = "The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is a therapeutic target for the treatment of hypercalcaemia of malignancy, Paget's disease and osteoporosis. In primates, the CTR is subject to alternative splicing, with a unique, primate-specific splice variant being preferentially expressed in reproductive organs, lung and kidney. In addition, humans possess a common non-synonymous single-nucleotide polymorphism (SNP) encoding a proline/leucine substitution in the C-terminal tail. In low power studies, the leucine polymorphism has been associated with increased risk of osteoporosis in East Asian populations and, independently, with increased risk of kidney stone disease in a central Asian population. The CTR is pleiotropically coupled, though the relative physiological importance of these pathways is poorly understood. Using both COS-7 and HEK293 cells recombinantly expressing human CTR, we have characterized both splice variant and polymorphism dependent response to CTs from several species in key signalling pathways and competition binding assays. These data indicate that the naturally occurring changes to the intracellular face of CTR alter ligand affinity and signalling, in a pathway and agonist dependent manner. These results further support the potential for these primate-specific CTR variants to engender different physiological responses. In addition, we report that the CTR exhibits constitutive internalization, independent of splice variant and polymorphism and this profile is unaltered by peptide binding.",
keywords = "Calcitonin, Calcitonin receptor, G protein-coupled receptor, Polymorphism, Splice variant",
author = "{Dal Maso}, Emma and Rasmus Just and Caroline Hick and Arthur Christopoulos and Sexton, {Patrick M.} and Denise Wootten and Furness, {Sebastian G.B.}",
year = "2018",
month = "2",
day = "1",
doi = "10.1016/j.bcp.2017.12.016",
language = "English",
volume = "148",
pages = "111--129",
journal = "Biochemical Pharmacology",
issn = "0006-2952",
publisher = "Elsevier",

}

Characterization of signalling and regulation of common calcitonin receptor splice variants and polymorphisms. / Dal Maso, Emma; Just, Rasmus; Hick, Caroline; Christopoulos, Arthur; Sexton, Patrick M.; Wootten, Denise; Furness, Sebastian G.B.

In: Biochemical Pharmacology, Vol. 148, 01.02.2018, p. 111-129.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Characterization of signalling and regulation of common calcitonin receptor splice variants and polymorphisms

AU - Dal Maso, Emma

AU - Just, Rasmus

AU - Hick, Caroline

AU - Christopoulos, Arthur

AU - Sexton, Patrick M.

AU - Wootten, Denise

AU - Furness, Sebastian G.B.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is a therapeutic target for the treatment of hypercalcaemia of malignancy, Paget's disease and osteoporosis. In primates, the CTR is subject to alternative splicing, with a unique, primate-specific splice variant being preferentially expressed in reproductive organs, lung and kidney. In addition, humans possess a common non-synonymous single-nucleotide polymorphism (SNP) encoding a proline/leucine substitution in the C-terminal tail. In low power studies, the leucine polymorphism has been associated with increased risk of osteoporosis in East Asian populations and, independently, with increased risk of kidney stone disease in a central Asian population. The CTR is pleiotropically coupled, though the relative physiological importance of these pathways is poorly understood. Using both COS-7 and HEK293 cells recombinantly expressing human CTR, we have characterized both splice variant and polymorphism dependent response to CTs from several species in key signalling pathways and competition binding assays. These data indicate that the naturally occurring changes to the intracellular face of CTR alter ligand affinity and signalling, in a pathway and agonist dependent manner. These results further support the potential for these primate-specific CTR variants to engender different physiological responses. In addition, we report that the CTR exhibits constitutive internalization, independent of splice variant and polymorphism and this profile is unaltered by peptide binding.

AB - The calcitonin receptor (CTR) is a class B G protein-coupled receptor that is a therapeutic target for the treatment of hypercalcaemia of malignancy, Paget's disease and osteoporosis. In primates, the CTR is subject to alternative splicing, with a unique, primate-specific splice variant being preferentially expressed in reproductive organs, lung and kidney. In addition, humans possess a common non-synonymous single-nucleotide polymorphism (SNP) encoding a proline/leucine substitution in the C-terminal tail. In low power studies, the leucine polymorphism has been associated with increased risk of osteoporosis in East Asian populations and, independently, with increased risk of kidney stone disease in a central Asian population. The CTR is pleiotropically coupled, though the relative physiological importance of these pathways is poorly understood. Using both COS-7 and HEK293 cells recombinantly expressing human CTR, we have characterized both splice variant and polymorphism dependent response to CTs from several species in key signalling pathways and competition binding assays. These data indicate that the naturally occurring changes to the intracellular face of CTR alter ligand affinity and signalling, in a pathway and agonist dependent manner. These results further support the potential for these primate-specific CTR variants to engender different physiological responses. In addition, we report that the CTR exhibits constitutive internalization, independent of splice variant and polymorphism and this profile is unaltered by peptide binding.

KW - Calcitonin

KW - Calcitonin receptor

KW - G protein-coupled receptor

KW - Polymorphism

KW - Splice variant

UR - http://www.scopus.com/inward/record.url?scp=85039787770&partnerID=8YFLogxK

U2 - 10.1016/j.bcp.2017.12.016

DO - 10.1016/j.bcp.2017.12.016

M3 - Article

VL - 148

SP - 111

EP - 129

JO - Biochemical Pharmacology

JF - Biochemical Pharmacology

SN - 0006-2952

ER -