GPCR Signaling From Intracellular Membranes − A Novel Concept

Stäubert, Claudia; Schöneberg, Torsten

doi:10.1002/bies.201700200

Cited by 8 publications

(7 citation statements)

References 5 publications

(7 reference statements)

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“…It is interesting to note that the natural DRY motif mutation in the RXFP3 has been associated with preferences for enhanced receptor internalization. It may be possible therefore that this internalized RXFP3 receptor pool could initiate distinct signaling modalities independent from that emanating from the plasma membrane [138, 139]. In this context, it is unsurprising that such a functional idiosyncrasy may be associated with a protein strongly linked to internalization behavior and microvesicular movement, i.e .…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…However, it has become clear that CB 1 receptors are also among the ever-growing list of GPCRs that are also located intracellularly. Studies have demonstrated functional CB 1 receptors associated with endosomes/lysosomes [108] and mitochondria [109][110][111][112]. In brain, about 30 % of the total CB 1 population was found to be located in the outer mitochondrial membrane of brain neuronal cells and astrocytes [109,110,[112][113][114].…”

Section: Effects Of Fatty Acids Through Endocannabinoid Signalingmentioning

confidence: 99%

Fatty Acids as Cell Signals in Ingestive Behaviors

Figlewicz

Witkamp

2020

Physiology & Behavior

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“…This classical view of receptor pharmacology is still valid, especially for rapid extracellular stimulator-based G protein activation. There is now considerable evidence however demonstrating that GPCRs can also signal from intracellular membranes such as endosomes, mitochondria, endoplasmic reticulum, Golgi apparatus and the nucleus [ 113 , 114 ]. This additional signaling capacity suggests that GPCRs also act as intracellular signal transducers for stimulatory factors generated inside the cell.…”

Section: G Protein-coupled Receptor Systems: Intersections With Dnmentioning

confidence: 99%

“…However, considerable emerging data suggest that actively signaling GPCRs are not solely associated with the plasma membrane. Instead, GPCR signaling can also emanate from various intracellular membrane structures and can display distinct signaling features such as diverse receptorsome structures, altered lipid environments or differential ‘stimulator’ sensitivities [ 113 , 121 , 255 , 256 , 257 ]. While the classical perspective that GPCRs can be activated at the plasma membrane and subsequently be transported to the intracellular membranes ( Model 1 ) still holds true, it is now evident that GPCRs can be activated at intracellular membranes through intracellularly-synthesized stimulators, as well as membrane-permeable or even endocytosed receptor ligands [ 256 ].…”

Section: The Gpcr-ddr Signaling Intersection and Its Potential Thementioning

confidence: 99%

G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

Leysen

Gastel

Hendrickx

et al. 2018

IJMS

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G protein-coupled receptors (GPCRs) and their associated proteins represent one of the most diverse cellular signaling systems involved in both physiological and pathophysiological processes. Aging represents perhaps the most complex biological process in humans and involves a progressive degradation of systemic integrity and physiological resilience. This is in part mediated by age-related aberrations in energy metabolism, mitochondrial function, protein folding and sorting, inflammatory activity and genomic stability. Indeed, an increased rate of unrepaired DNA damage is considered to be one of the ‘hallmarks’ of aging. Over the last two decades our appreciation of the complexity of GPCR signaling systems has expanded their functional signaling repertoire. One such example of this is the incipient role of GPCRs and GPCR-interacting proteins in DNA damage and repair mechanisms. Emerging data now suggest that GPCRs could function as stress sensors for intracellular damage, e.g., oxidative stress. Given this role of GPCRs in the DNA damage response process, coupled to the effective history of drug targeting of these receptors, this suggests that one important future activity of GPCR therapeutics is the rational control of DNA damage repair systems.

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GPCR Signaling From Intracellular Membranes − A Novel Concept

Cited by 8 publications

References 5 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

Fatty Acids as Cell Signals in Ingestive Behaviors

G Protein-Coupled Receptor Systems as Crucial Regulators of DNA Damage Response Processes

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