Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration

Cheng, Lan; Al‐Owais, Moza M.; Covarrubias, Manuel; Koch, Walter J.; Manning, David R.; Peers, Chris; Galdo, Natalia A. Riobo-Del

doi:10.1074/jbc.ra118.001989

Cited by 11 publications

(8 citation statements)

References 29 publications

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“…Almost all of these GPCRs belong to the Glutamate and Rhodopsin families (Offermanns and Rosenthal, 2008), but some receptors of the F/Frizzled/smoothened family also have been reported to couple to G i/o . These include G i -coupled smoothened receptors signaling for Sonic Hedghog (Polizio et al, 2011a,b; Carbe et al, 2014; Cheng et al, 2018; Ho Wei et al, 2018) and Frizzled 6 Wnt receptor (Kilander et al, 2014a,b; Arthofer et al, 2016). Noteworthy, all these receptors may couple differentially among different G i and G o isoforms, and specifically prefer one specific isoform to the other(s) (Jiang et al, 2001, 2002; Jiang and Bajpayee, 2009; Wang et al, 2011; Tang et al, 2012), a topic that should be further explored by researchers.…”

Section: Brain-enriched Gpcrs Coupled To Gi/omentioning

confidence: 99%

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: Brain-enriched Gpcrs Coupled To Gi/omentioning

confidence: 99%

Gi/o-Protein Coupled Receptors in the Aging Brain

Oliveira

Ramos

et al. 2019

Front. Aging Neurosci.

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“…GLI1 and GLI2 act to drive the expression of GLI-target genes, while GLI3 serves as a transcriptional repressor. Hh signalling has also been reported to trigger the activation of RhoA/Rac1 activity and the inhibition of voltage-dependent Kv channels [13,14]. A wealth of studies indicate that Hh and Wnt signalling cascades crosstalk with the TGF-β pathway at multiple levels in positive feedback loops.…”

Section: Introductionmentioning

confidence: 99%

Induction of Pro-Fibrotic CLIC4 in Dermal Fibroblasts by TGF-β/Wnt3a Is Mediated by GLI2 Upregulation

Wasson

Caballero-Ruiz

Gillespie

et al. 2022

Cells

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Chloride intracellular channel 4 (CLIC4) is a recently discovered driver of fibroblast activation in Scleroderma (SSc) and cancer-associated fibroblasts (CAF). CLIC4 expression and activity are regulated by TGF-β signalling through the SMAD3 transcription factor. In view of the aberrant activation of canonical Wnt-3a and Hedgehog (Hh) signalling in fibrosis, we investigated their role in CLIC4 upregulation. Here, we show that TGF-β/SMAD3 co-operates with Wnt3a/β-catenin and Smoothened/GLI signalling to drive CLIC4 expression in normal dermal fibroblasts, and that the inhibition of β-catenin and GLI expression or activity abolishes TGF-β/SMAD3-dependent CLIC4 induction. We further show that the expression of the pro-fibrotic marker α-smooth muscle actin strongly correlates with CLIC4 expression in dermal fibroblasts. Further investigations revealed that the inhibition of CLIC4 reverses morphogen-dependent fibroblast activation. Our data highlights that CLIC4 is a common downstream target of TGF-β, Hh, and Wnt-3a through signalling crosstalk and we propose a potential therapeutic avenue using CLIC4 inhibitors

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“…A non-canonical role of SMO as a G protein-coupled receptor (14, 15) provides a mechanism to control PKA activity. Upon stimulation, SMO activates heterotrimeric G i proteins, which, upon dissociation, inhibit adenylate cyclase through the Gα subunit to reduce cAMP production and PKA activation [ 15 , 47 , 48 ]. Therefore, SMO inhibition can lead to increased cAMP-mediated PKA activity accounting for SMO modification of the Ubr5 mt phenotype, as impairment of either UBR5 or SMO leads to increased cAMP-mediated PKA activity–with their combined impairment leading to either additive or synergistic effects.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis

et al. 2021

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Mammalian Hedgehog (HH) signalling pathway plays an essential role in tissue homeostasis and its deregulation is linked to rheumatological disorders. UBR5 is the mammalian homologue of the E3 ubiquitin-protein ligase Hyd, a negative regulator of the Hh-pathway in Drosophila. To investigate a possible role of UBR5 in regulation of the musculoskeletal system through modulation of mammalian HH signaling, we created a mouse model for specific loss of Ubr5 function in limb bud mesenchyme. Our findings revealed a role for UBR5 in maintaining cartilage homeostasis and suppressing metaplasia. Ubr5 loss of function resulted in progressive and dramatic articular cartilage degradation, enlarged, abnormally shaped sesamoid bones and extensive heterotopic tissue metaplasia linked to calcification of tendons and ossification of synovium. Genetic suppression of smoothened (Smo), a key mediator of HH signalling, dramatically enhanced the Ubr5 mutant phenotype. Analysis of HH signalling in both mouse and cell model systems revealed that loss of Ubr5 stimulated canonical HH-signalling while also increasing PKA activity. In addition, human osteoarthritic samples revealed similar correlations between UBR5 expression, canonical HH signalling and PKA activity markers. Our studies identified a crucial function for the Ubr5 gene in the maintenance of skeletal tissue homeostasis and an unexpected mode of regulation of the HH signalling pathway.

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Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K+ currents in cardiomyocytes and prolongs cardiac action potential duration

Cited by 11 publications

References 29 publications

Gi/o-Protein Coupled Receptors in the Aging Brain

Gi/o-Protein Coupled Receptors in the Aging Brain

Induction of Pro-Fibrotic CLIC4 in Dermal Fibroblasts by TGF-β/Wnt3a Is Mediated by GLI2 Upregulation

Ubiquitin-protein ligase Ubr5 cooperates with hedgehog signalling to promote skeletal tissue homeostasis

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