The receptor for parathyroid hormone (PTH) and PTH-related protein (PTHrP) is a member of a subfamily of G-protein-coupled receptors. This subfamily includes receptors for calcitonin, secretin, vasoactive intestinal polypeptide, glucagon, and related peptides, growth hormone-releasing hormone, and pituitary adenylate cyclase activating peptide. These receptors couple agonist occupancy to activation of adenylate cyclase and, in some cases, to increases in Cai2+, but the molecular basis of signalling is unclear Mutagenesis studies of recombinant PTH/PTHrP receptors indicates that large portions of the third intracellular loop and C-terminal tail can be deleted and/or mutated without major loss of receptor-G-protein interaction, as evidenced by high affinity ligand binding and signal transduction. However, specific determinants in these domains appear to modulate the efficiency of effector activation. Further studies are needed to define the contact sites for PTH/PTHrP receptor-G-protein interaction.