Multidimensional informatic deconvolution defines gender-specific roles of hypothalamic GIT2 in aging trajectories

Gastel, Jaana van; Cai, Huan; Wang, Cong; Chadwick, Wayne; Daimon, Caitlin M.; Leysen, Hanne; Hendrickx, Jhana O.; Schepper, Robin De; Vangenechten, Laura; Turnhout, Jens Van; Verswyvel, Jasper; Becker, Kevin G.; Zhang, Yongqing; Lehrmann, Elin; Wood, William H.; Martin, Bronwen; Maudsley, Stuart

doi:10.1016/j.mad.2019.111150

Cited by 9 publications

(6 citation statements)

References 161 publications

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“…In this study, multiple tissues, from the central nervous system (cortex, hippocampus and hypothalamus) and the periphery (pancreas and liver) were collected from male GIT2KO mice for mRNA expression profiling (Figure 1A), where we found a strong connection between GIT2 and RXFP3 expression, replicating what we have previously seen for murine GIT2 heterozygous KO hypothalamic extracts [34]. To validate these mRNA expression findings, we performed western blots to assess RXFP3 protein expression patterns in multiple GIT2KO mice (Figure 1B).…”

Section: Resultssupporting

confidence: 82%

The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

Gastel

Leysen

Santos‐Otte

et al. 2019

Aging

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DNA damage response (DDR) processes, often caused by oxidative stress, are important in aging and -related disorders. We recently showed that G protein-coupled receptor (GPCR) kinase interacting protein 2 (GIT2) plays a key role in both DNA damage and oxidative stress. Multiple tissue analyses in GIT2KO mice demonstrated that GIT2 expression affects the GPCR relaxin family peptide 3 receptor (RXFP3), and is thus a therapeutically-targetable system. RXFP3 and GIT2 play similar roles in metabolic aging processes. Gaining a detailed understanding of the RXFP3-GIT2 functional relationship could aid the development of novel anti-aging therapies. We determined the connection between RXFP3 and GIT2 by investigating the role of RXFP3 in oxidative stress and DDR. Analyzing the effects of oxidizing (H2O2) and DNA-damaging (camptothecin) stressors on the interacting partners of RXFP3 using Affinity Purification-Mass Spectrometry, we found multiple proteins linked to DDR and cell cycle control. RXFP3 expression increased in response to DNA damage, overexpression, and Relaxin 3-mediated stimulation of RXFP3 reduced phosphorylation of DNA damage marker H2AX, and repair protein BRCA1, moderating DNA damage. Our data suggests an RXFP3-GIT2 system that could regulate cellular degradation after DNA damage, and could be a novel mechanism for mitigating the rate of age-related damage accumulation.

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Section: Resultssupporting

confidence: 82%

The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

Gastel

Leysen

Santos‐Otte

et al. 2019

Aging

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“…Indeed, many of the first aging-regulating genes discovered in species such as C. elegans were nearly all associated with the insulinotropic system [81,82]. Given this, it is also interesting to note that the metabolic underpinning of nearly all diseases is now apparent, demonstrating the importance of therapeutic intervention in these systems [83][84][85][86][87][88][89][90][91][92]. From an intervention standpoint, simple lifestyle modifications have subsequently demonstrated that caloric restriction (CR) can be effective in controlling the glucometabolic system to attenuate the incidence and magnitude of aging-related disease [93][94][95][96][97][98][99].…”

Section: Nutrient Sensingmentioning

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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“…In addition to the classical mode of G protein-dependent signaling an expanding repertoire of additional GPCR signaling adaptors, e.g., β-arrestin, has been gaining traction as an attractive new paradigm for effective novel drug development [1,6,8,13,[15][16][17]. Along with the β-arrestin signaling capacity, the novel GPCR adaptor, GIT2 (ADP-ribosylation factor GTPase-activating protein 2), has shown promise for its association with stressresponse functions of cells [6,18,19]. GIT2 is a central regulator of the aging process and has been shown to control multiple aspects of this process, including energy metabolism, mitochondrial function, circadian rhythm, immune senescence, central nervous system connectivity, and DNA damage management [6,[20][21][22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

Maudsley

Schrauwen

Harputluoğlu

et al. 2023

IJMS

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G protein-coupled receptors (GPCRs) play a significant role in controlling biological paradigms such as aging and aging-related disease. We have previously identified receptor signaling systems that are specifically associated with controlling molecular pathologies associated with the aging process. Here, we have identified a pseudo-orphan GPCR, G protein-coupled receptor 19 (GPR19), that is sensitive to many molecular aspects of the aging process. Through an in-depth molecular investigation process that involved proteomic, molecular biological, and advanced informatic experimentation, this study found that the functionality of GPR19 is specifically linked to sensory, protective, and remedial signaling systems associated with aging-related pathology. This study suggests that the activity of this receptor may play a role in mitigating the effects of aging-related pathology by promoting protective and remedial signaling systems. GPR19 expression variation demonstrates variability in the molecular activity in this larger process. At low expression levels in HEK293 cells, GPR19 expression regulates signaling paradigms linked with stress responses and metabolic responses to these. At higher expression levels, GPR19 expression co-regulates systems involved in sensing and repairing DNA damage, while at the highest levels of GPR19 expression, a functional link to processes of cellular senescence is seen. In this manner, GPR19 may function as a coordinator of aging-associated metabolic dysfunction, stress response, DNA integrity management, and eventual senescence.

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Multidimensional informatic deconvolution defines gender-specific roles of hypothalamic GIT2 in aging trajectories

Cited by 9 publications

References 161 publications

The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

The RXFP3 receptor is functionally associated with cellular responses to oxidative stress and DNA damage

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

GPR19 Coordinates Multiple Molecular Aspects of Stress Responses Associated with the Aging Process

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