title: Human calcitonin receptors exhibit agonist-independent (constitutive) signaling activity.
abstract: The human CT receptor (hCTR), which is found as three isoforms, belongs to a small, recently described subfamily of G protein-coupled receptors (GPCRs). Several mutant GPCRs have been shown to exhibit constitutive (or agonist-independent) signaling activity and cause disease in humans, but only a few GPCRs have been identified with agonist-independent activity in the wild-type (or native) form. In the hCTR subfamily, no wild-type receptor has been shown to exhibit constitutive activity and only one, a mutated receptor for PTH/PTH-related peptide, has been found with constitutive activity to cause disease in humans. We demonstrate that two wild-type isoforms of hCTR, hCTR-1 and hCTR-2, exhibit constitutive activity by showing that they cause elevation of cAMP and induction of a cAMP-responsive gene in two cell types in culture in the absence of agonist. The identical mutation that caused the PTH/PTH-related peptide receptor to be constitutively active was made in hCTR-2 and shown to have no effect on signaling. We suggest that constitutive activity of wild-type hCTR-1 and hCTR-2 may reflect an adaptation of their signaling properties to exert their regulatory function in the absence of agonist in some cell types.
authors.affiliation: Department of Medicine, Cornell University Medical College and The New York Hospital, New York, New York 10021, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Cohen
authors.forename: C N
authors.initials: CN
authors.lastname: Thaw
authors.forename: A
authors.initials: A
authors.lastname: Varma
authors.forename: M C
authors.initials: MC
authors.lastname: Gershengorn
authors.forename: D R
authors.initials: DR
authors.lastname: Nussenzveig
mesh_terms: D000818:Animals; D019556:COS Cells; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004285:Dogs; D006639:Histidine / Q000032:analysis; D006801:Humans; D016296:Mutagenesis; D010281:Parathyroid Hormone / Q000235:genetics; D018003:Receptors, Calcitonin / Q000235:genetics / Q000502:physiology*; D018016:Receptors, Parathyroid Hormone / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D010281:Parathyroid Hormone; D018003:Receptors, Calcitonin; D018016:Receptors, Parathyroid Hormone; D006639:Histidine; D000242:Cyclic AMP