Gi-mediated activation of the p21ras-mitogen-activated protein kinase pathway by alpha 2-adrenergic receptors expressed in fibroblasts.

Alblas, J.; Corven, E J van; Hordijk, Peter L.; Milligan, Graeme; Moolenaar, Wouter H.

doi:10.1016/s0021-9258(18)41514-1

Cited by 220 publications

(17 citation statements)

References 31 publications

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“…Thereafter, neutrophils that have emigrated into the interstitial tissue migrate toward the in flammatory sites by the gradient of chemoattrac tants. Most chemoattractant receptors expressed on neutrophils are coupled with the heterotri meric G i protein, which inhibits protein kinase A (PKA) and activates p42/44 extracellular signalregulated kinase (ERK) through both the  and  subunits of G i (Alblas et al, 1993;Howe and Marshall, 1993;Winitz et al, 1993).…”

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confidence: 99%

In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines

Mizuno

Kamioka

Kabashima

et al. 2014

Journal of Experimental Medicine

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confidence: 99%

In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines

Mizuno

Kamioka

Kabashima

et al. 2014

Journal of Experimental Medicine

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“…Both α 2A -AR and CB 1 -R are well-known modulators of ERK activation. In non-neuronal cultured cells, α 2A -AR agonists stimulate MAPK pathway via Gαi protein-dependent mechanisms [27,28]. However, α 2A -AR-mediated ERK activation in primary neuronal cultures or brain tissue is debated [29,30], with some studies showing an inhibitory effect on ERK signaling [31,32].…”

Section: Introductionmentioning

confidence: 99%

Effects of Gαi2 and Gαz protein knockdown on alpha2A-adrenergic and cannabinoid CB1 receptor regulation of MEK-ERK and FADD pathways in mouse cerebral cortex

2021

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Background Alpha 2A -adrenergic (α 2A -AR) and cannabinoid CB 1 (CB 1 -R) receptors exert their functions modulating multiple signaling pathways, including MEK-ERK (extracellular signal-regulated kinases) and FADD (Fas-associated protein with death domain) cascades. These molecules are relevant in finding biased agonists with fewer side effects, but the mechanisms involving their modulations by α 2A -AR-and CB 1 -R in vivo are unclear. This study investigated the roles of Gαi 2 and Gαz proteins in mediating α 2A -AR-and CB 1 -R-induced alterations of MEK-ERK and FADD phosphorylation (p-) in mouse brain cortex. Methods Gαi 2 or Gαz protein knockdown was induced in mice with selective antisense oligodeoxinucleotides (ODNs; 3 nmol/day, 5 days) prior to UK-14,304 (UK or brimonidine; 1 mg/kg) or WIN55212-2 (WIN; 8 mg/kg) acute treatments. Inactivated (p-T 286 ) MEK1, activated (p-S 217/221 ) MEK1/2, activated (p-T 202 /Y 204 ) ERK1/2, p-S 191 FADD, and the corresponding total forms of these proteins were quantified by immunoblotting. Results Increased (+ 88%) p-T 286 MEK1 cortical density, with a concomitant reduction (-43%) of activated ERK was observed in UK-treated mice. Both effects were attenuated by Gαi 2 or Gαz antisense ODNs. Contrastingly, WIN induced Gαi 2 -and Gαz-independent upregulations of p-T 286 MEK1 (+ 63%), p-S 217/221 MEK1/2 (+ 86%), and activated ERK (+ 111%) in brain. Pro-apoptotic FADD was downregulated (− 34 to 39%) following UK and WIN administration, whereas the neuroprotective p-S 191 FADD was increased (+ 74%) in WIN-treated mice only. None of these latter effects required from Gαi 2 or Gαz protein integrity. ConclusionThe results indicate that α 2A -AR (UK), but not CB 1 -R (WIN), agonists use Gαi 2 and Gαz proteins to modulate MEK-ERK, but not FADD, pathway in mouse brain cortex.

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“…However, a2 adrenoceptors are also able to regulate the activity of a number of other effectors. In a variety of circumstances z2-adrenoceptor agonists are able to inhibit Ca2+ currents [4], and, at least in situations in which a2 adenoceptors have been expressed heterologously, reports of the regulation of K+-channel flux [5], of stimulation of each of adenylate cyclase [6], of phospholipases of each of the A2 [7], C [8] and D [9] classes and of the mitogenactivated protein (MAP) kinase cascade [10], have been recorded.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the relative interactions between the α2C10 adrenoceptor and the guanine-nucleotide-binding proteins Go1α and Gi2α following co-expression of these polypeptides in rat 1 fibroblasts

Grassie

Milligan

1995

Biochemical Journal

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Rat 1 fibroblasts which had been transfected to express the human alpha 2C10 adrenoceptor (clone 1C) were further co-transfected with a plasmid containing the hygromycin-B-resistance gene and a plasmid containing a cDNA encoding the alpha-subunit of the rat pertussis-toxin-sensitive G-protein G(o)1. In clone 3 the receptor was expressed at some 2.2 pmol/mg of membrane protein, and G(o)1 alpha at approx. 100 pmol/mg of membrane protein. The interaction of these two polypeptides and that between the receptor and Gi2 alpha (endogenously expressed at some 50 pmol/mg of membrane protein) were studied. Agonist activation of G(o)1 alpha was observed in membranes of the alpha 2C10-adrenoceptor(+)-G(o)1 alpha+ cells (clone 3), but not in alpha 2C10-adrenoceptor(+)-G(o)alpha-cells (clone 1C), whereas similar agonist-dependent activation of Gi2 alpha was observed in both cell types. alpha 2C10-adrenoceptor activation of G(o)1 alpha and Gi2 alpha in clone-3 membranes was produced with similar agonist-dose-effect curves. These observations indicate that the receptor interacts with equivalent affinity with each of these G-proteins. Agonist-dependent cholera-toxin-catalysed [32P]ADP-ribosylation of G(o)1 alpha was terminated when the alpha 2-adrenoceptor antagonist yohimbine was added subsequent to agonist-induced initiation of the reaction and release of GDP, demonstrating the conformational requirement for this reaction to be the ternary complex of agonist-occupied receptor and guanine-nucleotide-denuded G-protein.

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Gi-mediated activation of the p21ras-mitogen-activated protein kinase pathway by alpha 2-adrenergic receptors expressed in fibroblasts.

Cited by 220 publications

References 31 publications

In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines

In vivo imaging reveals PKA regulation of ERK activity during neutrophil recruitment to inflamed intestines

Effects of Gαi2 and Gαz protein knockdown on alpha2A-adrenergic and cannabinoid CB1 receptor regulation of MEK-ERK and FADD pathways in mouse cerebral cortex

Analysis of the relative interactions between the α2C10 adrenoceptor and the guanine-nucleotide-binding proteins Go1α and Gi2α following co-expression of these polypeptides in rat 1 fibroblasts

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