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Review
, 17, 1265-1277
eCollection

G Protein-Coupled Receptor Systems and Their Role in Cellular Senescence

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Review

G Protein-Coupled Receptor Systems and Their Role in Cellular Senescence

Paula Santos-Otte et al. Comput Struct Biotechnol J.

Abstract

Aging is a complex biological process that is inevitable for nearly all organisms. Aging is the strongest risk factor for development of multiple neurodegenerative disorders, cancer and cardiovascular disorders. Age-related disease conditions are mainly caused by the progressive degradation of the integrity of communication systems within and between organs. This is in part mediated by, i) decreased efficiency of receptor signaling systems and ii) an increasing inability to cope with stress leading to apoptosis and cellular senescence. Cellular senescence is a natural process during embryonic development, more recently it has been shown to be also involved in the development of aging disorders and is now considered one of the major hallmarks of aging. G-protein-coupled receptors (GPCRs) comprise a superfamily of integral membrane receptors that are responsible for cell signaling events involved in nearly every physiological process. Recent advances in the molecular understanding of GPCR signaling complexity have expanded their therapeutic capacity tremendously. Emerging data now suggests the involvement of GPCRs and their associated proteins in the development of cellular senescence. With the proven efficacy of therapeutic GPCR targeting, it is reasonable to now consider GPCRs as potential platforms to control cellular senescence and the consequently, age-related disorders.

Keywords: ADP-ribosylation factor GTPase-activating protein, (Arf-GAP); AT1R blockers, (ARB); Aging; Angiotensin II, (Ang II); Ataxia telangiectasia mutated, (ATM); Cellular senescence; G protein-coupled receptor kinase interacting protein 2 (GIT2); G protein-coupled receptor kinase interacting protein 2, (GIT2); G protein-coupled receptor kinase, (GRK); G protein-coupled receptors (GPCRs); G protein-coupled receptors, (GPCRs); Hutchinson–Gilford progeria syndrome, (HGPS); Lysophosphatidic acid, (LPA); Regulator of G-protein signaling, (RGS); Relaxin family receptor 3, (RXFP3); active state, (R*); angiotensin type 1 receptor, (AT1R); angiotensin type 2 receptor, (AT2R); beta2-adrenergic receptor, (β2AR); cyclin-dependent kinase 2, (CDK2); cyclin-dependent kinase inhibitor 1, (cdkn1A/p21); endothelial cell differentiation gene, (Edg); inactive state, (R); latent semantic indexing, (LSI); mitogen-activated protein kinase, (MAPK); nuclear factor kappa-light-chain-enhancer of activated B cells, (NF- κβ); protein kinases, (PK); purinergic receptors family, (P2Y); renin-angiotensin system, (RAS); retinoblastoma, (RB); senescence associated secretory phenotype, (SASP); stress-induced premature senescence, (SIPS); transcription factor E2F3, (E2F3); transmembrane, (TM); tumor suppressor gene PTEN, (PTEN); tumor suppressor protein 53, (p53); vascular smooth muscle cells, (VSMC); β-Arrestin.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Unlabelled Image
Fig. 1
Fig. 1
Mechanisms of cellular senescence. Two different types of cellular senescence exist, namely replicative senescence and stress-induced premature senescence (SIPS). SIPS can be induced by a wide variety of stressors, e.g. DNA damage, mitochondrial dysfunction and inflammation. In the presence of DNA damage, Ataxia telangiectasia mutated (ATM) is recruited to the sites of damage. This DNA association induces ATM auto-phosphorylation, ATM phosphorylation of subsequent additional targets as well as activation of p53. This activation causes the upregulation of the p53 transcriptional target (p21). This upregulation results in the inhibition of Rb in a CDK2 dependent manner, leading to cell cycle arrest in either the G1 or G2/M phase. p53 can be furthermore activated in a non-DNA damage dependent manner through loss of the tumor suppressor gene PTEN, stabilization of p19Arf, expression of the oncogenic gene Ras or overexpression of the S-phase transcription factor E2F3. Another mechanism of inducing senescence is through the activation of CDKN2A causing inhibition of the Rb family members in CDK4 or CDK6 dependent manner.
Fig. 2
Fig. 2
GPCR signaling systems. (A) Ligand binding causes receptor activation resulting in the stimulation of associated G proteins. This activation causes dissociation in to Gβγ-subunits and the Gα-subunits bound to GTP. Subsequent second messengers can be activated through both the Gβγ-subunits and the Gα-subunits. Termination of G-protein signaling is initiated through a GRK or PK dependent phosphorylation of the C-terminal tail of the GPCR. This phosphorylation results in the recruitment of β-arrestin to the GPCR, following internalization of the receptor. The internalized receptor can then be either recycled back to the plasma membrane or undergo lysosomal degradation. (B) The classical view of GPCR signaling diversity suggests that differential signaling outcomes are induced by sequential effector promiscuity linked to a single stimulated receptor. (C) Recent insights in GPCR signaling indicated that diversity is likely generated through the formation of stable receptor complexes. These different receptor complexes then define a diverse set of pre-organized signaling outcomes.
Fig. 3
Fig. 3
Functional intersection of the GPCR-senescence system. (A) Using the BioGrid database (https://thebiogrid.org/) the interacting proteins of several GPCR associated proteins were extracted and assembled into one GPCR-system protein list (red). A cellular senescence associated protein list (blue) was generated using the Reactome Pathway database (https://reactome.org/). (B) Here we show the number of overlapping proteins between the GPCR-system protein (red) list and the cellular senescence associated protein lists (blue). (C) The distribution of the 26 GPCR-senescence overlapping proteins originating from the different GPCR-associated factors are visualized in the donut plot. (D) Next, Enrichr (http://amp.pharm.mssm.edu/Enrichr/) was used to perform pathway analysis of these 26 overlapping proteins, showing cellular senescence as the most enriched pathway in this dataset. Probability (P)-values for each significantly populated signaling pathway are shown in the parentheses. (E) The proteins common to GPCR-associated proteins and cellular senescence were used for further analysis using Textrous! (https://textrous.irp.nia.nih.gov/), which employs latent semantic indexing to achieve a highly data-dependent unbiased appreciation of our data. The biomedical terms semantically associated with the 26-protein input dataset are organized into an agglomerative hierarchical cloud in which the strongest associations are denoted by increased font size and green-to-red color intensity. (F) Lastly we assessed the potential physical relationship with the NetworkAnalyst platform (https://www.networkanalyst.ca/). This platform uses protein-protein interaction analysis by using data extracted from the IMEx consortium (The International Molecular Exchange Consortium) consortium (https://www.imexconsortium.org/). A generic, zero-order, network was created using the 26 overlapping proteins. This data shows that the network is centered upon ubiquitin C (UBC) and is furthermore strongly associated with TRAF6-associated SASP functionality. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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