Gender Differences and Hormonal Modulation of G Proteins Gα&lt;sub&gt;q/11&lt;/sub&gt; Expression in Lymphoid Organs

Morton, Terri; Ansari, Mansoor A.; Jacobson, Jill D.

doi:10.1159/000072796

Cited by 9 publications

(6 citation statements)

References 22 publications

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“…This is in contrast with other studies that found a lower Gnaq expression in RA lymphocytes (Wang et al, 2012). Interestingly, there is also a gender bias as the expression of Gnaq increases in an oestrogen-dependent manner in immune cells (Morton et al, 2003).…”

Section: Discussioncontrasting

confidence: 99%

Gα_q modulates the energy metabolism of osteoclasts

Chakraborty

Handrick

et al. 2022

Preprint

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The bacterial protein toxin Pasteurella multocida toxin (PMT) mediates RANKL-independent osteoclast differentiation. Although these osteoclasts are small, their resorptive activity is high and destroys the nasal turbinate bones of pigs. Analysis of the proteome of classical and toxin-derived osteoclasts showed that PMT induces the upregulation of metabolic pathways. This includes strong glycolytic activity, increased expression of GLUT1 and upregulation of the mTOR pathway. As OxPhos components are also expressed more efficiently, cells display increased mitochondrial respiration. We found that the heterotrimeric G protein Gαq plays a central role in this hypermetabolic cell activation. Gαq triggers mitochondrial relocalisation of pSerSTAT3 and an increase in OPA1 expression. Overexpression of Gαq in Hoxb8 cells mimicked this hypermetabolic phenotype and resulted in higher glycolytic and mitochondrial activity as well as increased bone resorptive activity. Rheumatoid arthritis patients show an increase in Gnaq expression especially in the synovial fluid, suggesting that Gαq is a target of pathophysiological relevance.

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Section: Discussioncontrasting

confidence: 99%

Gα_q modulates the energy metabolism of osteoclasts

Chakraborty

Handrick

et al. 2022

Preprint

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“…We have observed similar self-priming effects of GnRH in immune cells. We have recently demonstrated that both estrogen and GnRH are able to induce GnRH's primary signal transducers, namely, the homologous G proteins, G␣ q and G␣ 11, in immune cells in mice (17,43). We speculate that GnRH-deficient mice, which are deficient in both estrogen and GnRH, may have a relative insufficiency of these stimulatory G proteins.…”

Section: Discussionmentioning

confidence: 96%

Immunomodulatory Actions of Gonadal Steroids May Be Mediated by Gonadotropin-Releasing Hormone

Jacobson

Ansari

2004

Endocrinology

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Estrogens are considered to be immunostimulatory, whereas androgens are considered to be immunosuppressive. We hypothesized that the divergent actions of gonadal steroids on the immune system may be mediated indirectly, via their potent divergent feedback effects on the hypothalamic hormone GnRH, which is itself immunostimulatory. We used the GnRH-deficient HPG/Bm mouse in an effort to disentangle the effects of gonadal steroids from the effects of GnRH. We randomized GnRH-deficient mice and their GnRH-sufficient littermates to receive androgens, estrogens, or GnRH. We subsequently measured B and T cell proliferative responses to mitogen and serum IgG levels. We demonstrate that estrogens exert stimulatory effects on B cell proliferation and serum IgG levels in the presence of GnRH but not in the absence of GnRH. Testosterone exerts suppressive effects on B cell function in the presence of GnRH but not in its absence. Androgens and estrogens exerted divergent actions on T cell function irrespective of the presence and absence of GnRH, although responses were markedly attenuated in GnRH-deficient mice. Our data suggest that the immunostimulatory effects of estrogen and the immunosuppressive effects of androgens on B cell function may be mediated indirectly via GnRH.

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“…This is in contrast with other studies that found a lower GNAQ expression in RA lymphocytes ( Wang et al., 2012 ). Interestingly, there is also a gender bias as the expression of GNAQ increases in an oestrogen-dependent manner in immune cells ( Morton et al., 2003 ). In addition, as outlined above, the metabolic regulation of lymphocytes and macrophages from RA patients is fundamentally different.…”

Section: Discussionmentioning

confidence: 99%

Gαq modulates the energy metabolism of osteoclasts

Chakraborty

Handrick

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionThe bacterial protein toxin Pasteurella multocida toxin (PMT) mediates RANKL-independent osteoclast differentiation. Although these osteoclasts are smaller, their resorptive activity is high which helps in efficient destruction of nasal turbinate bones of pigs.MethodsThe proteome of bone marrow-derived macrophages differentiated into osteoclasts with either RANKL or PMT was analysed. The results were verified by characterizing the metabolic activity using Seahorse analysis, a protein translation assay, immunoblots, real-time PCR as well as flow cytometry-based monitoring of mitochondrial activity and ROS production. A Gαq overexpression system using ER-Hoxb8 cells was used to identify Gαq-mediated metabolic effects on osteoclast differentiation and function.ResultsPMT induces the upregulation of metabolic pathways, which included strong glycolytic activity, increased expression of GLUT1 and upregulation of the mTOR pathway. As OxPhos components were expressed more efficiently, cells also displayed increased mitochondrial respiration. The heterotrimeric G protein Gαq plays a central role in this hypermetabolic cell activation as it triggers mitochondrial relocalisation of pSerSTAT3 and an increase in OPA1 expression. This seems to be caused by a direct interaction between STAT3 and OPA1 resulting in enhanced mitochondrial respiration. Overexpression of Gαq mimicked the hypermetabolic phenotype observed for PMT-induced osteoclasts and resulted in higher glycolytic and mitochondrial activity as well as increased bone resorptive activity. In addition, rheumatoid arthritis (RA) patients showed an increase in GNAQ expression, especially in the synovial fluid.DiscussionOur study suggests that Gαq plays a key role in PMT-induced osteoclastogenesis. Enhanced expression of GNAQ at the site of inflammation in RA patients indicates its pathophysiological relevance in the context of inflammatory bone disorders.

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Gender Differences and Hormonal Modulation of G Proteins Gα<sub>q/11</sub> Expression in Lymphoid Organs

Cited by 9 publications

References 22 publications

Gα_q modulates the energy metabolism of osteoclasts

Gα_q modulates the energy metabolism of osteoclasts

Immunomodulatory Actions of Gonadal Steroids May Be Mediated by Gonadotropin-Releasing Hormone

Gαq modulates the energy metabolism of osteoclasts

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