The PTH receptor type 1. The PTH receptor type 1. This “snake” diagram of the human the PTHR1 illustrates the receptor's 593 amino acids in a topological arrangement typical of the family B GPCRs. The receptor thus has a relatively large amino ECD of about 160 amino acids (minus the 23 amino acids of the N-terminal signal sequence) that are involved in initial ligand binding, the seven helical transmembrane domains and connecting loops that mediate agonist-induced receptor activation and signal transduction events, and a C-terminal tail of about 130 amino acids that contains sites involved in mediating ligand-induced receptor internalization, trafficking, and signal termination events. Key specific amino acids identified include the four pairs of extracellular cysteine (C) residues that form a disulfide bond network that is conserved in the family B GPCRs and maintains receptor structure and function (Lee et al., 1994; Pioszak and Xu, 2008; Pioszak et al., 2009); four glycosylated asparagine (N) residues in the ECD (Zhou et al., 2000); Thr33 and Gln37, which modulate interaction with tryptophan-23 in the ligand (Mannstadt et al., 1998; Mann et al., 2008); Phe184 and Arg186, which mediate interactions involving ligand residues at or near lysine-13 (Adams et al., 1998; Carter et al., 1999a); Ser370, Ile371, Met425, Trp437, and Gln440, which contribute interactions involving ligand residues at or near valine-2 and likely play a role in receptor activation (Gardella et al., 1994; Lee et al., 1995; Bisello et al., 1998; Behar et al., 1999; Gensure et al., 2001a); Arg233 and Gln451, which participate in an interhelical interaction network (dashed connectors) that likely helps modulate PTHR activation (Gardella et al., 1996a) and is conserved in the family B GPCRs (Hollenstein et al., 2013); conserved Pro132 in the ECD, which is the site of an inactivating mutation (Leu) in Blomstrand’s chondrodysplasia (Zhang et al., 1998); His223, Thr410, and Ile458, at which mutations result in constitutive signaling activity and in patients result in Jansen’s chondrodysplasia (Schipani et al., 1999); Lys319, at which mutations impair Gαq signaling (Iida-Klein et al., 1997); Lys388, at which mutations impair Gαq and Gαs signaling (Huang et al., 1996). Key residues in the C-tail include the seven serine (S) residues that are phosphorylated upon agonist activation and mediate recruitment of β-arrestins (Malecz et al., 1998; Qian et al., 1998; Tawfeek et al., 2002; Vilardaga et al., 2002; Rey et al., 2006) and the C-terminal ETVM sequence that mediates interaction with the NHERF family of proteins (Mahon et al., 2002, 2003; Ardura et al., 2011; Mamonova et al., 2012). In each transmembrane domain, the residue identified as the most conserved residue among the family B GPCRs is enclosed in a hexagon (Wootten et al., 2013). Thomas J. Gardella, and Jean-Pierre Vilardaga Pharmacol Rev 2015;67:310-337 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics