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Review
. 2011 Jan;68(1):1-13.
doi: 10.1007/s00018-010-0465-9. Epub 2010 Aug 12.

Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm

Jean-Pierre Vilardaga  1 , Guillermo Romero, Peter A Friedman, Thomas J Gardella
Affiliations
Review

Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm

Jean-Pierre Vilardaga et al. Cell Mol Life Sci. 2011 Jan.

Abstract

The parathyroid hormone (PTH) receptor type 1 (PTHR), a G protein-coupled receptor (GPCR), transmits signals to two hormone systems-PTH, endocrine and homeostatic, and PTH-related peptide (PTHrP), paracrine-to regulate different biological processes. PTHR responds to these hormonal stimuli by activating heterotrimeric G proteins, such as G(S) that stimulates cAMP production. It was thought that the PTHR, as for all other GPCRs, is only active and signals through G proteins on the cell membrane, and internalizes into a cell to be desensitized and eventually degraded or recycled. Recent studies with cultured cell and animal models reveal a new pathway that involves sustained cAMP signaling from intracellular domains. Not only do these studies challenge the paradigm that cAMP production triggered by activated GPCRs originates exclusively at the cell membrane but they also advance a comprehensive model to account for the functional differences between PTH and PTHrP acting through the same receptor.

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Figures

Fig. 1
Fig. 1
PTH and PTHrP bind and stimulate the same receptor to mediate divergent functions. PTH is rapidly secreted from the chief cells in parathyroid gland in response to small decreases in Ca2+ in the blood to restore a normal calcium level (≈1.2 mM) by promoting the release of calcium from bone and calcium reabsorption from the kidney. PTHrP is produced and secreted from many tissues and plays a critical role in tissue development, in particular the skeleton and mammary glands
Fig. 2
Fig. 2
General principle of signaling by PTHR. Following ligand binding, the receptor undergoes conformational changes, which promote the coupling with heterotrimeric G proteins (Gαβγ), and catalyzes the exchange of GDP for GTP on the α-subunit. This event triggers conformational and/or dissociation events between the α- and βγ subunits. GαS activates adenylyl cyclases leading to cAMP synthesis, which in turn activates protein kinase A (PKA). Gαq activates phospholipase C, which cleaves phosphatidylinositol (4,5)-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol (1,4,5)-trisphosphate (IP3). IP3 then diffuses through the cytosol and activates IP3-gated Ca2+ channels in the membranes of the endoplasmic reticulum, causing the release of stored Ca2+ into the cytosol. The increase of cytosolic Ca2+ promotes PKC translocation to the plasma membrane, and then activation by DAG
Fig. 3
Fig. 3
Mechanistic model for PTHR activation. Upon PTH(1–34) binding, there are two rates of association, a faster one that corresponds to agonist binding to the receptor N-domain and is strictly concentration-dependent, followed by a slower binding step to the receptor J-domain that is coupled to receptor activation. The hormone binds to and stabilizes the R0 conformation of PTHR, which in turn locks PTH into a high-affinity complex with the receptor. L PTH, R PTHR, LR 0 a high-affinity complex between the ligand and the PTHR, LR*G and LR*G* active states for receptor and G protein state, respectively. Time constants (τ) to accomplish each step are given in seconds
Fig. 4
Fig. 4
Carboxy-terminal PTHR binding motifs. The sequence of the intracellular tail of the human PTHR is shown. Described binding motifs are designated by boxed and colored notation. References are indicated in superscript
Fig. 5
Fig. 5
Mode of activation of the PTHR by long-acting and short-acting signaling ligands. The action of a short-acting signaling ligand is well represented by the classical model for G protein signaling. The ligand interacts first with the receptor (step 1). The receptor is then switched on to lead to G protein recruitment (step 2) and activation (step 3), which in turn initiates adenylyl cyclase activation. In the classical model—that is, the PTHrP-like hormone model—the ligand rapidly dissociates from the receptor, which deactivates and ultimately terminates the signaling. In our model for a long-acting signaling ligand such as PTH, the hormone interacts tightly with the receptor in a conformationally dependent manner. The receptor is then locked into a prolonged active state inducing sustained receptor-G protein coupling and sustained G protein activation. The ternary ligand–receptor-G protein heterocomplex is preserved during its internalization in early endosomes and persists over time to mediate the prolonged downstream signaling of PTH-like hormone. Images represent a 3D view of TMR-labeled ligands and the PTHR N terminally tagged with GFP (GFPN-PTHR) captured in live HEK-293 cells by spinning disc confocal microscopy 20 min after ligand wash out. PTH(1−34)TMR (red) and GFPN-PTHR (green) co-localized within endocytic compartments (right). In contrast, PTHrP(1−36)TMR alone is detected as small punctae at internalized sites (left). Adapted from Ref. [85]
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