PTH/PTHrP Receptor Signaling, Allostery, and Structures

Sutkevičiūtė, Ieva; Clark, Lisa J.; White, Anna Marie; Gardella, Thomas J.; Vilardaga, Jean-Pierre

doi:10.1016/j.tem.2019.07.011

Cited by 58 publications

(62 citation statements)

References 61 publications

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“…A significant ( P = 0.02) reduction in PTH H9A binding to the G protein-independent state of PTHR (R 0 ) 22 , a conformation thought to promote β-arrestin coupling 23 , was also observed. Thus, PTH H9A signals exclusively from the plasma membrane and cannot trigger the previously discovered endosomal PTHR signaling via cAMP 23 , 24 . Our data also indicate that the PTH His9 → Ala point mutation stabilizes a distinct receptor conformation that selectively engages acute plasma membrane cAMP signals while preventing endosomal cAMP signaling.…”

Section: Resultsmentioning

confidence: 93%

“…All unbiased simulations began with PTHR in an active conformation, as the LA-PTH–PTHR–Gs structure was used as a template to generate initial models 9 . This structure was a more favorable starting point than the inactive crystal structure of PTHR 25 , which contained several thermostabilizing mutations and a 196-residue Pyrococcus abysii glycogen synthase fusion to ICL3 that promoted the crystallization of an inactive conformation 24 , 25 . While the inward movement of ICL3 in apo and PTH H9A -bound PTHR simulations could be viewed as a first step toward transitioning to inactive state, the outward position of TM6, a signature of class B GPCRs in the active state, was maintained in these simulations.…”

Section: Resultsmentioning

confidence: 99%

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Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation

Clark¹,

Krieger²,

White³

et al. 2020

Nat Chem Biol

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation

Clark¹,

Krieger²,

White³

et al. 2020

Nat Chem Biol

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“…In agreement with this finding, injection of a long-acting PTH (LA-PTH) analog into mice causes prolonged hypercalcemic responses that correlate with the propensity to promote sustained cAMP from endosomes (8). Despite significant advancements in identifying the physiological relevance of PTHR endosomal signaling (5,9), its underlying molecular mechanisms and regulation remain incompletely understood. We recently reported on the development of G s -biased PTH analogs that stimulate cAMP production but fail to engage in endosomal cAMP signaling due to impaired recruitment of βarrestins (βarrs) (10).…”

mentioning

confidence: 91%

G _q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

White

Jean-Alphonse

Fang

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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cAMP production upon activation of Gs by G protein-coupled receptors has classically been considered to be plasma membrane-delimited, but a shift in this paradigm has occurred in recent years with the identification of several receptors that continue to signal from early endosomes after internalization. The molecular mechanisms regulating this aspect of signaling remain incompletely understood. Here, we investigated the role of Gq/11 activation by the parathyroid hormone (PTH) type 1 receptor (PTHR) in mediating endosomal cAMP responses. Inhibition of Gq/11 signaling by FR900359 markedly reduced the duration of PTH-induced cAMP production, and this effect was mimicked in cells lacking endogenous Gαq/11. We determined that modulation of cAMP generation by Gq/11 occurs at the level of the heterotrimeric G protein via liberation of cell surface Gβγ subunits, which, in turn, act in a phosphoinositide-3 kinase-dependent manner to promote the assembly of PTHR–βarrestin–Gβγ signaling complexes that mediate endosomal cAMP responses. These results unveil insights into the spatiotemporal regulation of Gs-dependent cAMP signaling.

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“…Despite the capacity of PTH to prolong endosomal cAMP signaling via a unique receptor conformation named R 0 (reviewed in Ref. 40), our structural understanding of endosomal GPCR signaling via G proteins is incomplete. The recent development of structural approaches to study mechanisms of GPCR activation (41) via cryo-EM, which will be discussed in the following paragraphs, however, opens new possibilities to unveil the exact underpinnings of endosomal GPCR signaling.…”

Section: Brief History Of the Concept Of Endosomal Gpcr Signaling Viamentioning

confidence: 99%

Structural insights into emergent signaling modes of G protein–coupled receptors

Sutkevičiūtė

Vilardaga

2020

Journal of Biological Chemistry

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G protein–coupled receptors (GPCRs) represent the largest family of cell membrane proteins, with >800 GPCRs in humans alone, and recognize highly diverse ligands, ranging from photons to large protein molecules. Very important to human medicine, GPCRs are targeted by about 35% of prescription drugs. GPCRs are characterized by a seven-transmembrane α-helical structure, transmitting extracellular signals into cells to regulate major physiological processes via heterotrimeric G proteins and β-arrestins. Initially viewed as receptors whose signaling via G proteins is delimited to the plasma membrane, it is now recognized that GPCRs signal also at various intracellular locations, and the mechanisms and (patho)physiological relevance of such signaling modes are actively investigated. The propensity of GPCRs to adopt different signaling modes is largely encoded in the structural plasticity of the receptors themselves and of their signaling complexes. Here, we review emerging modes of GPCR signaling via endosomal membranes and the physiological implications of such signaling modes. We further summarize recent structural insights into mechanisms of GPCR activation and signaling. We particularly emphasize the structural mechanisms governing the continued GPCR signaling from endosomes and the structural aspects of the GPCR resensitization mechanism, and discuss the recently uncovered and important roles of lipids in these processes.

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PTH/PTHrP Receptor Signaling, Allostery, and Structures

Cited by 58 publications

References 61 publications

Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation

Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation

G _q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

Structural insights into emergent signaling modes of G protein–coupled receptors

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PTH/PTHrP Receptor Signaling, Allostery, and Structures

Cited by 58 publications

References 61 publications

Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation

Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation

G q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR

Structural insights into emergent signaling modes of G protein–coupled receptors

Contact Info

Product

Resources

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G _q/11 -dependent regulation of endosomal cAMP generation by parathyroid hormone class B GPCR