β2-adrenergic receptor control of endosomal PTH receptor signaling via Gβγ

Jean-Alphonse, Frédéric; Wehbi, Vanessa L.; Chen, Jingming; Noda, Masaki; Taboas, Juan M.; Xiao, Kunhong; Vilardaga, Jean-Pierre

doi:10.1038/nchembio.2267

Cited by 54 publications

(54 citation statements)

References 35 publications

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“…However, in this case, trafficking appears to occur through the biosynthetic pathway and it is not known if the AC-containing compartment also contains a relevant GPCR or G protein. We also note that AC2 and AC3 contribute to cAMP signaling by Gs-coupled polypeptide hormone receptors after endocytosis in mammalian cells (Jean-Alphonse et al, 2017; Kriebel et al, 2008), but the trafficking properties of these AC isoforms remain to be delineated. Moreover, a distinct AC isoform that lacks any transmembrane domains (‘soluble’ AC or AC10) contributes to the cellular cAMP response elicited by another Gs-coupled GPCR from endosomes (Inda et al, 2016).…”

Section: Discussionmentioning

confidence: 93%

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Lazar

Irannejad

Baldwin³

et al. 2020

Preprint

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SummaryGPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report dynamic trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes, while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs or Gs. AC9 transits a similar dynamin-dependent early endocytic pathway as activated GPCRs but, in contrast to GPCR trafficking which is regulated by β-arrestin but not Gs, AC9 trafficking is regulated by Gs but not β-arrestin. We also show that AC9, but not AC1, contributes to cAMP production from endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in controlling subcellular location of a relevant effector.

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Section: Discussionmentioning

confidence: 93%

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Lazar

Irannejad

Baldwin³

et al. 2020

Preprint

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“…In keratinocytes, CaSRs are co‐localized with PLC‐1 ATP‐Ca 2+ transporter and IP 3 ‐receptor in Golgi apparatus . PPR has been shown to activate adenylate cyclase in endosomes to increase cytosolic cAMP concentration . In the growth plate, PTHrP maintains the proliferative state of chondrocyte and prevents their terminal differentiation through the action of PPR .…”

Section: Discussionmentioning

confidence: 99%

“…(42) PPR has been shown to activate adenylate cyclase in endosomes to increase cytosolic cAMP concentration. (43,44) In the growth plate, PTHrP maintains the proliferative state of chondrocyte and prevents their terminal differentiation through the action of PPR. (40) The CaSR signaling antagonizes these PTHrP/PPR actions to promote chondrocytes' terminal differentiation.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR

Zhang

Yang

Wan

et al. 2018

Journal of Bone and Mineral Research

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Traumatic joint injuries produce osteoarthritic cartilage manifesting accelerated chondrocyte terminal differentiation and matrix degradation via unknown cellular and molecular mechanisms. Here we report the ability of biomechanical stress to increase expression of the calcium‐sensing receptor (CaSR), a pivotal driver of chondrocyte terminal differentiation, in cultured chondrogenic cells subjected to fluid flow shear stress (FFSS) and in chondrocytes of rodent temporomandibular joint (TMJ) cartilage subjected to unilateral anterior cross‐bite (UAC). In cultured ATDC5 cells or TMJ chondrocytes, FFSS induced Ca2+ loading and CaSR localization in endoplasmic reticulum (ER), casually accelerating cell differentiation that could be abrogated by emptying ER Ca2+ stores or CaSR knockdown. Likewise, acute chondrocyte‐specific Casr knockout (KO) prevented the UAC‐induced acceleration of chondrocyte terminal differentiation and matrix degradation in TMJ cartilage in mice. More importantly, local injections of CaSR antagonist, NPS2143, replicated the effects of Casr KO in preventing the development of osteoarthritic phenotypes in TMJ cartilage of the UAC‐treated rats. Our study revealed a novel pathological action of CaSR in development of osteoarthritic cartilage due to aberrant mechanical stimuli and supports a therapeutic potential of calcilytics in preventing osteoarthritis in temporomandibular joints by targeting the CaSR. © 2018 American Society for Bone and Mineral Research.

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“…G is well established to activate distinct effectors at the plasma membrane, in this study, however, G released from G i, can stimulate endosomal adenylate cyclase 2 activity to prolong nuclear cAMP and PKA activity via an interesting mechanism involving crosstalk with the β2AR-mediated cAMP signaling pathway [66]. The source of G is proposed to be from G i at the plasma membrane that is coupled to…”

Section: The Early Endosome (Ee) As a Heterotrimeric G Protein Signalmentioning

confidence: 78%

Spatial encryption of G protein-coupled receptor signaling in endosomes; Mechanisms and applications

Sposini

Hanyaloglu

2017

Biochemical Pharmacology

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Within any cellular signaling system membrane trafficking is a critical mechanism for cells to translate complex networks into specific downstream responses, including the signal pathways activated by the superfamily of G protein-coupled receptors (GPCRs). Classically, membrane trafficking is viewed as a mechanism to regulate ligand sensitivity of a target tissue by controlling the level of surface receptors. Recent studies, however, have not only highlighted that GPCR trafficking is a tightly regulated process critical for spatio-temporal control of signaling, but that heterotrimeric G protein signaling can also be reactivated or continue to signal from distinct endocytic compartments, and even endosomal microdomains. The significance of spatio-temporal control will be discussed, not only with respect to how these novel molecular pathways impact our basic understanding of cellular regulation, but also our view of how aberrant signaling can result in disease. Furthermore, these mechanisms offer the potential application for novel therapeutic strategies to identify GPCR compounds with high specificity in their actions.

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β2-adrenergic receptor control of endosomal PTH receptor signaling via Gβγ

Cited by 54 publications

References 35 publications

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR

Spatial encryption of G protein-coupled receptor signaling in endosomes; Mechanisms and applications

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