Available online 20 November 2023, 112107

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Compartmentalization of GPCR signaling is an emerging topic that highlights the physiological relevance of spatial bias in signaling. The parathyroid hormone (PTH) type 1 receptor (PTH1R) was the first GPCR described to signal via heterotrimeric G-protein and cAMP from endosomes after β-arrestin mediated internalization, challenging the canonical GPCR signaling model which established that signaling is terminated by receptor internalization. More than a decade later, many other GPCRs have been shown to signal from endosomes via cAMP, and recent studies have proposed that location of cAMP generation impacts physiological outcomes of GPCR signaling. Here, we review the extensive literature regarding PTH1R endosomal signaling via cAMP, the mechanisms that regulate endosomal generation of cAMP, and the implications of spatial bias in PTH1R physiological functions.

Section snippetsImplications of PTH1R on human health

The parathyroid hormone (PTH) type 1 receptor (PTH1R) is a class B G protein-coupled receptor (GPCR) responsible for regulating skeletal development, bone remodeling, calcium homeostasis (Cheloha et al., 2015) and is the designated cell surface receptor of native agonists PTH and PTH-related protein (PTHrP) (Juppner et al., 1991) (Fig. 1). PTH is an endocrine peptide hormone comprised of 84 amino acids that is essential in regulating levels of ionized serum calcium (Ca2+) and phosphate (PO43−)

PTH1R endosomal signaling via heterotrimeric G-protein and cAMP

The concept of GPCR endosomal signaling first emerged in 2009 as a way to explain why certain peptide ligands exhibit prolonged cAMP responses in cells. The classical model of GPCR signaling assumes that production of cAMP takes place exclusively at the plasma membrane and is terminated when the receptor is removed from the cell surface via endocytosis, resulting in transient cAMP responses (Ferrandon et al., 2009). In this model (Fig. 2A), GPCR kinases (GRKs) phosphorylate the active receptor,

Regulation of endosomal cAMP production by Gq/11

Agonist-induced PTH1R activation triggers signaling via heterotrimeric Gs and Gq/11 proteins, activating cAMP/PKA and PLC/Ca2+ signaling pathways, respectively. While the importance of Gs in PTH1R endosomal signaling has been previously established (Wehbi et al., 2013), Gq/11 signaling has not been linked to sustained cAMP endosomal signaling until recently. The introduction of PTH backbone modifications, consisting of single α→β amino acid substitution (Liu et al., 2018), results in Gs-biased

Physiological implications PTH1R cAMP endosomal signaling

Recruitment of β-arrestin to PTH1R is a critical step in inducing endosomal PTH1R signaling (White et al., 2020), thus it is not surprising that several mechanisms are in place to regulate this step. Within PTH1-34, residues 4–13 are part of the signal selectivity epitope and are suggested to be important for β-arrestin recruitment to the receptor. As evidenced by ANM analyses, residues 5, 6, 7, 9, and 10 exhibit a high cross-correlation value with Thr392 of PTH1R ICL3, which is involved in PTH1

The role of glycosaminoglycans in location bias signaling

The N-terminal fragment of PTHrP (PTHrP1-36) elicits transient cAMP signaling that originates at the plasma membrane (Pena et al., 2022). Since most studies have been done using PTHrP1-36, little is known about how native PTHrP signals via PTH1R. However, a recent study unveiled the signaling properties of the native 141 amino acid PTHrP splice variant, referred to as PTHrP1-141 (Pena et al., 2022). Unlike PTHrP1-36, PTHrP1-141 induces sustained cAMP production from the plasma membrane, similar

Discussion and perspectives

Over the last decade, PTH1R has become a prototypic GPCR for studying cAMP singling from endosomes through G-protein activation. Following initial studies describing the ability of internalized PTH1R to generate cAMP from endosomes, many other GPCRs have been shown to also exhibit endosomal cAMP signaling (Table 1), challenging the GPCR signaling paradigm. PTH1R endosomal cAMP generation and subsequent physiological effects are highly regulated by the various mechanisms described in this

Declaration of competing interest

The autors report no conflict of interests.

Acknowledgments

This work was supported by NIH T32 grant for SS and NIH R01DK116780, R21 DE032478, R01DK122259, R01 HD100468 grants supporting KAP.

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© 2023 Published by Elsevier B.V.