The subcellular dynamics of GPCR signaling

Calebiro, Davide; Köszegi, Zsombor

doi:10.1016/j.mce.2018.12.020

Cited by 46 publications

(40 citation statements)

References 84 publications

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“…Indeed, several evidence have emerged supporting other activation models than the classical one, including observations that (1) GPCRs can form either hetero- or homodimers and create functional pre-coupled complexes with heterotrimeric G proteins in the rest state (Han et al, 2009; Parker et al, 2011; Ferre et al, 2014; Nishimura et al, 2017; Prieto, 2017; Durdagi et al, 2018; Navarro et al, 2018; Tóth et al, 2018; Calebiro and Koszegi, 2019); (2) the G proteins can exist in a pre-coupled complex with the GPCR and an effector protein, as AC; further, binding of agonists to GPCR might result in the activation of the G protein without its dissociation from the complex (Ferré, 2015; Navarro et al, 2018); (3) some G α subunits can interact and modulate downstream signaling even when bound to GDP (Kamakura et al, 2013; Lin et al, 2014); (4) newly identified modulators of G protein activity, called GEMs (guanine exchange modulators), can activate and inhibit different G α subunits through the same motif (Gupta et al, 2016; Ghosh et al, 2017).…”

Section: Heterotrimeric G Proteins Of the Gi/o Subfamilymentioning

confidence: 99%

“…The new knowledge on GPCR dynamics is thus a driving force in the research and development of new therapeutic drugs for age-associated diseases, from neurodegenerative to cardiovascular diseases, osteoporosis, type 2 diabetes mellitus, etc. (Guerram et al, 2016; Huang et al, 2017; Lütjens and Rocher, 2017; Tóth et al, 2018; van Gastel et al, 2018; Calebiro and Koszegi, 2019; Maroteaux et al, 2019). To achieve this goal it is necessary to understand how aging and age-associated disease impact other receptorsome components such as the downstream heterotrimeric G proteins.…”

Section: Age-induced Alterations In Brain-enriched Gi/o- Coupled Gpcrsmentioning

confidence: 99%

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Gi/o-Protein Coupled Receptors in the Aging Brain

Oliveira

Ramos

et al. 2019

Front. Aging Neurosci.

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Cells translate extracellular signals to regulate processes such as differentiation, metabolism and proliferation, via transmembranar receptors. G protein-coupled receptors (GPCRs) belong to the largest family of transmembrane receptors, with over 800 members in the human species. Given the variety of key physiological functions regulated by GPCRs, these are main targets of existing drugs. During normal aging, alterations in the expression and activity of GPCRs have been observed. The central nervous system (CNS) is particularly affected by these alterations, which results in decreased brain functions, impaired neuroregeneration, and increased vulnerability to neuropathologies, such as Alzheimer’s and Parkinson diseases. GPCRs signal via heterotrimeric G proteins, such as G o , the most abundant heterotrimeric G protein in CNS. We here review age-induced effects of GPCR signaling via the G i/o subfamily at the CNS. During the aging process, a reduction in protein density is observed for almost half of the G i/o -coupled GPCRs, particularly in age-vulnerable regions such as the frontal cortex, hippocampus, substantia nigra and striatum. G i/o levels also tend to decrease with aging, particularly in regions such as the frontal cortex. Alterations in the expression and activity of GPCRs and coupled G proteins result from altered proteostasis, peroxidation of membranar lipids and age-associated neuronal degeneration and death, and have impact on aging hallmarks and age-related neuropathologies. Further, due to oligomerization of GPCRs at the membrane and their cooperative signaling, down-regulation of a specific G i/o -coupled GPCR may affect signaling and drug targeting of other types/subtypes of GPCRs with which it dimerizes. G i/o -coupled GPCRs receptorsomes are thus the focus of more effective therapeutic drugs aiming to prevent or revert the decline in brain functions and increased risk of neuropathologies at advanced ages.

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Section: Heterotrimeric G Proteins Of the Gi/o Subfamilymentioning

confidence: 99%

Section: Age-induced Alterations In Brain-enriched Gi/o- Coupled Gpcrsmentioning

confidence: 99%

Gi/o-Protein Coupled Receptors in the Aging Brain

Oliveira

Ramos

et al. 2019

Front. Aging Neurosci.

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“…G-protein-coupled receptors (GPCRs) constitute one of the largest groups of receptors responsible for signal transmission [36,37,38]. GPCRs are composed of an N-terminal extracellular domain, seven transmembrane helices, and a C-terminal region directed to the cytosol.…”

Section: Cross-talk Between Fgfrs and G-protein-coupled Receptors mentioning

confidence: 99%

Cross-Talk between Fibroblast Growth Factor Receptors and Other Cell Surface Proteins

Latko

Czyrek

Porębska

et al. 2019

Cells

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Fibroblast growth factors (FGFs) and their receptors (FGFRs) constitute signaling circuits that transmit signals across the plasma membrane, regulating pivotal cellular processes like differentiation, migration, proliferation, and apoptosis. The malfunction of FGFs/FGFRs signaling axis is observed in numerous developmental and metabolic disorders, and in various tumors. The large diversity of FGFs/FGFRs functions is attributed to a great complexity in the regulation of FGFs/FGFRs-dependent signaling cascades. The function of FGFRs is modulated at several levels, including gene expression, alternative splicing, posttranslational modifications, and protein trafficking. One of the emerging ways to adjust FGFRs activity is through formation of complexes with other integral proteins of the cell membrane. These proteins may act as coreceptors, modulating binding of FGFs to FGFRs and defining specificity of elicited cellular response. FGFRs may interact with other cell surface receptors, like G-protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs). The cross-talk between various receptors modulates the strength and specificity of intracellular signaling and cell fate. At the cell surface FGFRs can assemble into large complexes involving various cell adhesion molecules (CAMs). The interplay between FGFRs and CAMs affects cell–cell interaction and motility and is especially important for development of the central nervous system. This review summarizes current stage of knowledge about the regulation of FGFRs by the plasma membrane-embedded partner proteins and highlights the importance of FGFRs-containing membrane complexes in pathological conditions, including cancer.

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“…The temporal patterns of TAAR1 activation revealed sustained Gs signaling. This long-lasting action, common among GPCRs, may derive either from persistent signaling (Calebiro and Koszegi, 2019), activation of the downstream cascades after agonist binding, or from persistent agonist-independent activation of the receptor itself (Thomsen et al, 2016). Persistent activation may lead to prolonged influences on cell—particularly neuron—activity and synapse efficacy (Panaccione et al, 2013; Young et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Non-Functional Trace Amine-Associated Receptor 1 Variants in Patients With Mental Disorders

et al. 2019

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Background: The G protein–coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR1) is expressed across brain areas involved in emotions, reward and cognition, and modulates monoaminergic and glutamatergic neurotransmissions. TAAR1 is stimulated with nanomolar affinity by 3-iodothyronamine (T1AM), an endogenous messenger considered a novel branch of thyroid hormone signaling. The human gene for TAAR1 maps to locus 6q23, within a region associated with major mental disorders. Materials and Methods: We screened a cohort of patients with major mental disorders (n = 104) and a group of healthy controls (n = 130) for TAAR1 variants. HEK293 cells were transiently transfected with: i) wild-type TAAR1 and ii) mutated TAAR1, either in homozygous or heterozygous state. Cell surface expression and Gs/adenylyl cyclase activation upon administration of β-phenylethylamine (PEA), T1AM, and RO5166017, were assessed. Results: We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs. 1, 1 variant in both groups, p < 0.01). In silico analysis identified four dysfunctional variants, all in patients. Three of these—R23C, Y131C, and C263R—were functionally characterized. In cells co-transfected with wild-type and mutated TAAR1, we observed a significant reduction of cell surface expression. In heterozygosity, the three TAAR1 variants substantially dampened Gs signaling in response to PEA, and, more robustly, to T1AM. Co-stimulation with PEA and RO5166017 did not yield any improvement in Gs signaling. R23C, Y131C, and C263R are rare in the general population and map in functionally important highly conserved positions across TAAR1 orthologous and paralogous genes. Conclusions: Our findings suggest that disruptions of TAAR1 activity may be relevant to the pathophysiology of mental disorders, thereby providing a promising target for novel psychopharmacological interventions.

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The subcellular dynamics of GPCR signaling

Cited by 46 publications

References 84 publications

Gi/o-Protein Coupled Receptors in the Aging Brain

Gi/o-Protein Coupled Receptors in the Aging Brain

Cross-Talk between Fibroblast Growth Factor Receptors and Other Cell Surface Proteins

Non-Functional Trace Amine-Associated Receptor 1 Variants in Patients With Mental Disorders

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