Aging-related modifications to G protein-coupled receptor signaling diversity

Gastel, Jaana van; Leysen, Hanne; Boddaert, Jan; Vangenechten, Laura; Luttrell, Louis M.; Martin, Bronwen; Maudsley, Stuart

doi:10.1016/j.pharmthera.2020.107793

Cited by 14 publications

(15 citation statements)

References 419 publications

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“…Advances in the molecular understanding of GPCR signaling complexity have expanded their therapeutic capacity tremendously [114][115][116][117][118]. Thus, emerging data now suggest the involvement of GPCRs and their physically associating adaptor proteins in the development of cellular senescence [119][120][121]. With the proven efficacy of therapeutic GPCR targeting, it is reasonable to now consider GPCRs as potential platforms for controlling cellular senescence and aging-related disorders.…”

Section: Cell Senescencementioning

confidence: 99%

The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease

Leysen

Walter

Clauwaert

et al. 2022

IJMS

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During the aging process our body becomes less well equipped to deal with cellular stress, resulting in an increase in unrepaired damage. This causes varying degrees of impaired functionality and an increased risk of mortality. One of the most effective anti-aging strategies involves interventions that combine simultaneous glucometabolic support with augmented DNA damage protection/repair. Thus, it seems prudent to develop therapeutic strategies that target this combinatorial approach. Studies have shown that the ADP-ribosylation factor (ARF) GTPase activating protein GIT2 (GIT2) acts as a keystone protein in the aging process. GIT2 can control both DNA repair and glucose metabolism. Through in vivo co-regulation analyses it was found that GIT2 forms a close coexpression-based relationship with the relaxin-3 receptor (RXFP3). Cellular RXFP3 expression is directly affected by DNA damage and oxidative stress. Overexpression or stimulation of this receptor, by its endogenous ligand relaxin 3 (RLN3), can regulate the DNA damage response and repair processes. Interestingly, RLN3 is an insulin-like peptide and has been shown to control multiple disease processes linked to aging mechanisms, e.g., anxiety, depression, memory dysfunction, appetite, and anti-apoptotic mechanisms. Here we discuss the molecular mechanisms underlying the various roles of RXFP3/RLN3 signaling in aging and age-related disorders.

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Section: Cell Senescencementioning

confidence: 99%

The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease

Leysen

Walter

Clauwaert

et al. 2022

IJMS

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“…Moreover, the NHERF2 isoform can also activate the Gi-protein, which additionally inhibits adenylyl-cyclase and cAMP-dependent signaling ( Wang et al, 2010 ; Broadbent et al, 2017 ). Age-associated changes in NHERF-dependent mechanisms of regulation of intracellular signaling from PTHR1 may be associated with the development of osteoporosis ( van Gastel et al, 2021 ). Thus, the adapter proteins associated with the receptors can switch intracellular signaling activated in different cells by the same hormone and its receptor.…”

Section: Main Textmentioning

confidence: 99%

“…For example, glucagon-like peptide 1 (GLP1), which is an important regulator of nutrient homeostasis, regulates the balance between adipogenic and osteogenic differentiation of MSCs in a β -arrestin/Erk-dependent manner ( Lee et al, 2015 ). Age-related changes in the regulation of β -arrestin–dependent internalization of GLP1 receptor may play a role in the development of type II diabetes ( van Gastel et al, 2021 ). Intracellular signaling activated on endosomes by β -arrestin usually has a lower amplitude and longer duration than G-protein–dependent signals from the receptor ( Figure 2 ) ( Luttrell and Gesty-Palmer, 2010 ).…”

Section: Main Textmentioning

confidence: 99%

GPCRs in the regulation of the functional activity of multipotent mesenchymal stromal cells

Chechekhin

Kulebyakin²,

Kokaev³

et al. 2022

Front. Cell Dev. Biol.

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Adipose tissue is one of the tissues in the human body that is renewed during the whole life. Dysregulation of this process leads to conditions such as obesity, metabolic syndrome, and type 2 diabetes. The key role in maintaining the healthy state of adipose tissue is played by a specific group of postnatal stem cells called multipotent mesenchymal stromal cells (MSCs). They are both precursors for new adipocytes and key paracrine regulators of adipose tissue homeostasis. The activity of MSCs is tightly adjusted to the needs of the organism. To ensure such coordination, MSCs are put under strict regulation which is realized through a wide variety of signaling mechanisms. They control aspects of MSC activity such as proliferation, differentiation, and production of signal molecules via alteration of MSC sensitivity to hormonal stimuli. In this regard, MSCs use all the main mechanisms of hormonal sensitivity regulation observed in differentiated cells, but at the same time, several unique regulatory mechanisms have been found in MSCs. In the presented review, we will cover these unique mechanisms as well as specifics of common mechanisms of regulation of hormonal sensitivity in stem cells.

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“…The GPCR transmembrane superfamily is characterized by a common seven α-helical transmembrane domain motifs. GPCRs represent one of the most therapeutically important molecular targets in clinical medicine [ 1 , 2 , 3 , 4 ]. GPCRs facilitate communication between cells in tissues across long distances in the body, thereby enabling the capacity for systems-level therapeutic actions [ 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process

Maudsley

Walter

Schrauwen

et al. 2022

IJMS

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G protein-coupled receptors (GPCRs) represent one of the most functionally diverse classes of transmembrane proteins. GPCRs and their associated signaling systems have been linked to nearly every physiological process. They also constitute nearly 40% of the current pharmacopeia as direct targets of remedial therapies. Hence, their place as a functional nexus in the interface between physiological and pathophysiological processes suggests that GPCRs may play a central role in the generation of nearly all types of human disease. Perhaps one mechanism through which GPCRs can mediate this pivotal function is through the control of the molecular aging process. It is now appreciated that, indeed, many human disorders/diseases are induced by GPCR signaling processes linked to pathological aging. Here we discuss one such novel member of the GPCR family, GPR19, that may represent an important new target for novel remedial strategies for the aging process. The molecular signaling pathways (metabolic control, circadian rhythm regulation and stress responsiveness) associated with this recently characterized receptor suggest an important role in aging-related disease etiology.

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Aging-related modifications to G protein-coupled receptor signaling diversity

Cited by 14 publications

References 419 publications

The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease

The Relaxin-3 Receptor, RXFP3, Is a Modulator of Aging-Related Disease

GPCRs in the regulation of the functional activity of multipotent mesenchymal stromal cells

Intersection of the Orphan G Protein-Coupled Receptor, GPR19, with the Aging Process

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