Figure 1 Altered modes of cAMP signalling at PTHR1

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Figure 1 Altered modes of cAMP signalling at PTHR1 Altered modes of cAMP signalling at PTHR1. Structurally distinct PTH and PTHrP ligands can bind preferentially to two different high affinity receptor conformations, R0 and RG, and thereby induce different modes of GαS-mediated cAMP signalling (inset, lower panel). RG-selective ligands (for example PTHrP) induce transient cAMP responses that are derived from signalling complexes localized at the plasma membrane, whereas R0-selective ligands (for example certain PTH analogues) can also induce prolonged cAMP responses that are derived from complexes associated within endosomes. The internalized signalling complexes contain β-arrestin, which promotes, rather than terminates cAMP signalling by activating ERK1/2, leading to the inhibition of PDE4 enzymes. Termination of endosomal signalling correlates with an exchange at the complex of β-arrestin for retromer sorting proteins, and is promoted by vATPase-mediated vesicle acidification. The vATPases are activated by cAMP-dependent PKA, and thereby establish a negative feedback loop. PTHR1 activation of cAMP signalling that differs in duration and location of origin within the cell provides a potential mechanism for ligand-directed diversification of cellular responses. Abbreviations: ERK1/2, extracellular signal-regulated protein kinase 1/2; PDE4, phosphodiesterase 4; PKA, protein kinase A; PTH, parathyroid hormone; PTHR1, PTH/PTHrP type 1 receptor; PTHrP, parathyroid hormone-related protein; R0, G-protein-independent conformational state; RG, G-protein-dependent conformational state; vATPase, vacuolar H+-ATPase. Cheloha, R. W. et al. (2015) PTH receptor-1 signalling—mechanistic insights and therapeutic prospects Nat. Rev. Endocrinol. doi:10.1038/nrendo.2015.139