Constitutive Activities and Inverse Agonism in Dopamine Receptors

Zhang, Boyang; Albaker, Awatif; Plouffe, Bianca; Lefèbvre, Caroline; Tiberi, Mario

doi:10.1016/b978-0-12-417197-8.00007-9

Cited by 47 publications

(46 citation statements)

References 181 publications

(169 reference statements)

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“…Thus, the GPER seems to harbor a constitutive (intrinsic) activity and implies an “inverse agonism” profile for ERα17p [57,58]. The intrinsic activity of the GPCR is well-documented [59,60,61]. In the same context, we have shown that the GPER antagonist G-36 was able to reduce the anti-proliferative potency of ERα17p (Figure 1A).…”

Section: Discussionmentioning

confidence: 70%

The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells

Lappano

Mallet

Rizzuti

et al. 2019

Cells

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The inhibition of the G protein-coupled estrogen receptor (GPER) offers promising perspectives for the treatment of breast tumors. A peptide corresponding to part of the hinge region/AF2 domain of the human estrogen receptor α (ERα17p, residues 295–311) exerts anti-proliferative effects in various breast cancer cells including those used as triple negative breast cancer (TNBC) models. As preliminary investigations have evoked a role for the GPER in the mechanism of action of this peptide, we focused our studies on this protein using SkBr3 breast cancer cells, which are ideal for GPER evaluation. ERα17p inhibits cell growth by targeting membrane signaling. Identified as a GPER inverse agonist, it co-localizes with GPER and induces the proteasome-dependent downregulation of GPER. It also decreases the level of pEGFR (phosphorylation of epidermal growth factor receptor), pERK1/2 (phosphorylation of extracellular signal-regulated kinase), and c-fos. ERα17p is rapidly distributed in mice after intra-peritoneal injection and is found primarily in the mammary glands. The N-terminal PLMI motif, which presents analogies with the GPER antagonist PBX1, reproduces the effect of the whole ERα17p. Thus, this motif seems to direct the action of the entire peptide, as highlighted by docking and molecular dynamics studies. Consequently, the tetrapeptide PLMI, which can be claimed as the first peptidic GPER disruptor, could open new avenues for specific GPER modulators.

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Section: Discussionmentioning

confidence: 70%

The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells

Lappano

Mallet

Rizzuti

et al. 2019

Cells

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“…Previous studies reporting D1R agonist–independent activity have used D1R mutants with diminished constitutive activity as genetic tools ( Zhang et al, 2014 ). We chose a single mutant, D1RS199A, that displays a very low level of constitutive activity but maintains the same expression levels and sensitivity to dopamine as WT D1R ( Al-Fulaij et al, 2008 ).…”

Section: Resultsmentioning

confidence: 99%

“…For instance, our laboratory has demonstrated that constitutive activity of two different GPCRs has a great impact on calcium channel function ( López Soto et al, 2015 ; Agosti et al, 2017 ; Mustafá et al, 2017 ; Martínez Damonte et al, 2018 ). For D1/D5R, there is an abundance of in vitro reports demonstrating a basal increase in Gs activity in several systems ( Plouffe et al, 2010 ; Zhang et al, 2014 ; Zhang et al, 2015 ). Our studies extend the role of D1R constitutive activity in a physiologically relevant event: the stimulation of mPFC native and recombinant Ca V 2.2 currents by D1R expression.…”

Section: Introductionmentioning

confidence: 99%

Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

McCarthy

Chou-Freed

Rodríguez

et al. 2020

Journal of General Physiology

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Alterations in dopamine receptor type 1 (D1R) density are associated with cognitive deficits of aging and schizophrenia. In the prefrontal cortex (PFC), D1R plays a critical role in the regulation of working memory, which is impaired in these cognitive deficit states, but the cellular events triggered by changes in D1R expression remain unknown. A previous report demonstrated that interaction between voltage-gated calcium channel type 2.2 (CaV2.2) and D1R stimulates CaV2.2 postsynaptic surface location in medial PFC pyramidal neurons. Here, we show that in addition to the occurrence of the physical receptor-channel interaction, constitutive D1R activity mediates up-regulation of functional CaV2.2 surface density. We performed patch-clamp experiments on transfected HEK293T cells and wild-type C57BL/6 mouse brain slices, as well as imaging experiments and cAMP measurements. We found that D1R coexpression led to ∼60% increase in CaV2.2 currents in HEK293T cells. This effect was occluded by preincubation with a D1/D5R inverse agonist, chlorpromazine, and by replacing D1R with a D1R mutant lacking constitutive activity. Moreover, D1R-induced increase in CaV2.2 currents required basally active Gs protein, as well as D1R-CaV2.2 interaction. In mice, intraperitoneal administration of chlorpromazine reduced native CaV currents’ sensitivity to ω-conotoxin-GVIA and their size by ∼49% in layer V/VI pyramidal neurons from medial PFC, indicating a selective effect on CaV2.2. Additionally, we found that reducing D1/D5R constitutive activity correlates with a decrease in the agonist-induced D1/D5R inhibitory effect on native CaV currents. Our results could be interpreted as a stimulatory effect of D1R constitutive activity on the number of CaV2.2 channels available for dopamine-mediated modulation. Our results contribute to the understanding of the physiological role of D1R constitutive activity and may explain the noncanonical postsynaptic distribution of functional CaV2.2 in PFC neurons.

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“…Activation of G protein-coupled receptors in glioblastoma cells could occur if the cells produce their own agonists such as dopamine. However this is not essential, as there is evidence for basal activity of G protein receptors, including dopamine receptors, in the absence of agonist [44, 45]. G protein-coupled receptors appear to spontaneously switch between inactive and active conformations, with agonists stabilizing the latter and inverse agonists stabilizing the former.…”

Section: Discussionmentioning

confidence: 99%

PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

et al. 2016

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A defining feature of the brain cancer glioblastoma is its highly invasive nature. When glioblastoma cells are isolated from patients using serum free conditions, they accurately recapitulate this invasive behaviour in animal models. The Rac subclass of Rho GTPases has been shown to promote invasive behaviour in glioblastoma cells isolated in this manner. However the guanine nucleotide exchange factors responsible for activating Rac in this context have not been characterized previously. PREX1 is a Rac guanine nucleotide exchange factor that is synergistically activated by binding of G protein αγ subunits and the phosphoinositide 3-kinase pathway second messenger phosphatidylinositol 3,4,5 trisphosphate. This makes it of particular interest in glioblastoma, as the phosphoinositide 3-kinase pathway is aberrantly activated by mutation in almost all cases. We show that PREX1 is expressed in glioblastoma cells isolated under serum-free conditions and in patient biopsies. PREX1 promotes the motility and invasion of glioblastoma cells, promoting Rac-mediated activation of p21-associated kinases and atypical PKC, which have established roles in cell motility. Glioblastoma cell motility was inhibited by either inhibition of phosphoinositide 3-kinase or inhibition of G protein βγ subunits. Motility was also inhibited by the generic dopamine receptor inhibitor haloperidol or a combination of the selective dopamine receptor D2 and D4 inhibitors L-741,626 and L-745,870. This establishes a role for dopamine receptor signaling via G protein βγ subunits in glioblastoma invasion and shows that phosphoinositide 3-kinase mutations in glioblastoma require a context of basal G protein–coupled receptor activity in order to promote this invasion.

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Constitutive Activities and Inverse Agonism in Dopamine Receptors

Cited by 47 publications

References 181 publications

The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells

The Peptide ERα17p Is a GPER Inverse Agonist that Exerts Antiproliferative Effects in Breast Cancer Cells

Constitutive activity of dopamine receptor type 1 (D1R) increases CaV2.2 currents in PFC neurons

PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

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