HUMAN CALCITONIN RECEPTORS EXHIBIT AGONIST-INDEPENDENT (CONSTITUTIVE)SIGNALING ACTIVITY

The human CT receptor (hCTR), which is found as three isoforms, belong s to a small, recently described subfamily of G protein-coupled recept ors (GPCRs). Several mutant GPCRs have been shown to exhibit constitut ive (or agonist-independent) signaling activity and cause disease in h umans, but only a few; GPCRs have been identified with agonist-indepen dent activity in the wild-type (or native) few. 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 bee n found with constitutive activity to cause disease in humans. We demo nstrate that two wild-type isoforms of hCTR, hCTR-1 and hCTR-2, exhibi t constitutive activity by showing that they cause elevation of cAMP a nd induction of a cAMP-responsive gene in two cell types in culture in the absence of agonist. The identical mutation that caused the PTH/PT H-related peptide receptor to be constitutively active was made in hCT R-2 and shown to have no effect on signaling. We suggest that constitu tive activity of wild-type hCTR-1 and hCTR-2 may reflect an adaptation of their signaling properties to exert their regulatory function in t he absence of agonist in some cell types.