Human Calcitonin Receptors Exhibit Agonist-Independent (Constitutive) Signaling Activity 1

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.