Gq-Coupled Receptors in Autoimmunity

Zhang, Lu; Shi, Guixiu

doi:https://doi.org/10.1155/2016/3969023

Journal of Immunology Research

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Abstract Introduction References Copyright Related Articles

Review Article | Open Access

Volume 2016 | Article ID 3969023 | https://doi.org/10.1155/2016/3969023

Gq-Coupled Receptors in Autoimmunity

Lu Zhang¹and Guixiu Shi²

Academic Editor: Xiao-Feng Yang

Received06 Oct 2015

Accepted27 Dec 2015

Published17 Jan 2016

Abstract

Heterotrimeric G proteins can be divided into Gi, Gs, Gq/11, and G12/13 subfamilies according to their α subunits. The main function of G proteins is transducing signals from G protein coupled receptors (GPCRs), a family of seven transmembrane receptors. In recent years, studies have demonstrated that GPCRs interact with Gq, a member of the Gq/11 subfamily of G proteins. This interaction facilitates the vital role of this family of proteins in immune regulation and autoimmunity, particularly for Gαq, which is considered the functional α subunit of Gq protein. Therefore, understanding the mechanisms through which Gq-coupled receptors control autoreactive lymphocytes is critical and may provide insights into the treatment of autoimmune disorders. In this review, we summarize recent advances in studies of the role of Gq-coupled receptors in autoimmunity, with a focus on their pathologic role and downstream signaling.

1. Introduction

Many receptors for hormones, neurotransmitters, neuropeptides, chemokines, and autocrine and paracrine signaling molecules interact with heterotrimeric G proteins to exert their actions on target cells [1]; these receptors are considered G protein coupled receptors (GPCRs) [2]. It is estimated that more than 800 GPCRs are encoded in the mammalian genome [3], supporting that GPCRs are common membrane receptors in cells.

Heterotrimeric G proteins consist of an α-subunit, which binds to and hydrolyzes guanosine-5′-triphosphate (GTP), and β- and γ-subunits, which form an indissociable complex [4]. GPCRs transmit extracellular signals into the cell by binding to and activating different intracellular signaling proteins, termed G proteins (Gαβγ, families Gi, Gs, Gq/11, G12/13) or arrestins [5]. The Gq proteins, like all heterotrimeric G proteins, are composed of three subunits: Gαq, Gβ, and Gγ [6]. Gαq-GTP and the Gβγ dimer then transmit receptor-generated signals to downstream effector molecules and protein binding partners until the intrinsic GTPase activity of Gα hydrolyzes GTP to GDP and the inactive subunits reassociate [6]; this is called the “active and inactive” cycle. Each of the four major subfamilies of G proteins is associated with different signaling pathways: Gq/11 activates the phospholipase C (PLC) family; Gs stimulates the adenylyl cyclase (AC) pathway; Gi/o inhibits AC; and G12/13 activates small GTPases [4].

The Gq/11 subfamily, including Gq, G11, G14, and G15/16, shares structural similarity, and activation of the α subunit within each protein complex can activate PLC-β [4–7]. Furthermore, all of these four subunits regulate both overlapping and distinct signaling pathways, thereby stimulating inositol lipid (i.e., calcium/protein kinase C (PKC)) signaling through PLC-β isoforms [1, 4–9]. Genetic studies using whole animal models have demonstrated the importance of Gq in cardiac, lung, brain, and platelet functions, helping to define the physiological and pathological processes mediated by the Gq [5, 10].

Recent studies have described all four subtypes of Gq/11 coupled GPCRs, including the muscarinic 1, 3, and 5 (M1, M3, and M5) receptors; bombesin receptor, vasopressin receptor, endothelin receptor, thyrotropin-releasing hormone receptor (TRHR), gonadotropin-releasing hormone receptor (GnRHR), membrane estrogen receptor (mER), chemokine receptors, adrenergic receptors (α1AR), and angiotensin II type 1 receptor (AT(1)R) [11–13]. In the field of immunology, chemokine and hormone receptors have been shown to function as Gq protein-coupled GPCRs. These GqPCRs are expressed on lymphocytes and are regulated by their ligands in the immune system [14–18]. Abnormal regulation of these receptors may be associated with the pathogenesis of autoimmunity and a variety of autoimmune diseases induced by autoreactive lymphocytes, leading to morbidity and mortality in individuals with autoimmune disorders [19–24].

2. The Diversity of Gq-Coupled Receptors in Autoimmunity

Gq is the most commonly studied subclass of the Gq/11 subfamily in the field of immunology [18] and is mainly coupled to sex hormone receptors and some chemokine receptors, which are differentially expressed in certain types of lymphocytes [6, 18] (Table 1).

2.1. The GnRHRs and mERs

Gonadotropin-releasing hormone (GnRH) is the primary hormone associated with reproduction; GnRH is known to exert its actions largely through two related Gq/11 protein receptors [25]. The interaction between GnRH and its cognate type I receptor (GnRHR) in the pituitary results in the activation of Gq, PLC-β, phospholipase A2 (PLA2), and phospholipase D (PLD) [2]. Sequential activation of phospholipases generates the second messengers inositol 1, 4,5-tris-phosphate (IP3), diacylglycerol (DAG), and arachidonic acid (AA), which are required for Ca²⁺ mobilization. Further activation of various protein kinase C isoforms (PKCs) induces sequential activation of mitogen-activated protein kinases (MAPKs) [26] and promotes nuclear transcription. GnRHR mRNA and protein have been found in the pituitary, lymphocytes, mononuclear cells, and various types of cancer cells [23]. Many autoimmune diseases, particularly systemic lupus erythematosus (SLE), exhibit gender-specific differences, and GnRHRs have been shown to function as immunostimulatory hormone receptors, playing pivotal roles in the observed gender-specific differences in immunity and/or autoimmunity [27].

Acute treatment with GnRH increases the expression of GnRHR mRNA in murine thymocytes [28]. Studies in mice and rats have shown that GnRH stimulates the expression of hormone-GqPCR and the interleukin- (IL-) 2 receptor, the proliferation of B and T lymphocytes, and the elevation of serum IgG levels [27]. Jacobson [23] measured GnRHR mRNA and GnRH binding in lupus-prone mice after in vivo exposure to GnRH or vehicle. Their results showed that even vehicle-treated females expressed more GnRHR in immune cells than did vehicle-treated males; gender differences were confirmed, with females expressing Gq-coupled hormone receptor mRNA and protein more than males [26]. In mice given GnRH, GnRH (through GqPCR) exacerbated lupus in vivo in females only [27]. Additional studies have shown that GnRH (through GqPCR) stimulates T/B lymphocyte proliferation in vitro in females only [29]. These differences in expression and activation of GnRHR through GqPCR on lymphocytes contribute to the observed gender differences in immunity and/or autoimmunity.

In addition to the pivotal function of intracellular estrogen receptors in autoimmunity, researchers have also shown that mERs can stimulate Gq-coupled GPCRs through PKC and calcium pathways [30]. Rider and Abdou [31] suggested that estrogen acting through Gq-mERs enhances T-cell activation in women with lupus, resulting in amplified T/B-cell interactions, B-cell activation, and autoantibody production.

Thus, the gender differences in GnRH and estrogen production and function can be directly associated with Gq protein receptor expression, which plays a critical role in maintaining the balance of T/B lymphocytes and affects the morbidity of autoimmune diseases that predominantly affect women.

2.2. The Chemokine Receptors

Chemokine receptors are expressed on T cells, B cells, monocytes, macrophages, and dendritic cells [32]. Chemokine receptors and their ligand axis play pivotal roles in leukocyte migration, differentiation, adhesion, and activation [32, 33]. Many chemokine receptors have been implicated in the pathogenesis of autoimmune connective tissue diseases such as SLE, rheumatoid arthritis (RA), and systemic sclerosis (SS) [19–21, 32, 34–37]. However, previous studies have demonstrated the indispensable role of chemokine receptors in autoimmune diseases, highlighting the role of Gi protein-coupled chemokine receptors (rather than Gq-coupled receptors) in directing the migration of immune cells, which mostly signal through the canonical AC pathway [19, 36].

In a cell-based study, Arai and Charo [32] showed that monocyte chemotactic protein- (MCP-) 1-related chemokine receptors (mainly CC family receptors) interact with multiple subtypes of G proteins in a cell type-specific manner and that the third intracellular loop of CC type receptors mediates Gq coupling.

Moreover, many studies have shown that chemokine receptors can interact with multiple G-protein subtypes; the coupling is cell type-specific [32]. Shi and colleagues [38] showed that chemokine receptors can be divided into CD38-dependent and -independent subclasses, depending on whether CD38 is needed for the chemotaxis of the ligand. CD38-dependent chemokine receptors couple to Gq, indicating that there is indeed a novel Gq protein-coupled alternative signaling pathway separate from the canonical Gi-coupled classic pathway.

Autoimmunity-associated chemokine receptors mainly include the CC family (CCR5 and CCR7) and the CXC family (CXCR3, CXCR4, CXCR5, and CXCR7) [19, 20, 34, 36–41]. To date, most chemokine receptors, such as CXCR4 and CXCR5 on T cells and B cells, have been shown to be induced by Gi in the classic pathway, while CCR7 and CXCR4 have been shown to be dependent on Gq pathways only on dendritic cells (DCs) [38]. Hence, the dependence of autoimmune diseases on the specific Gq coupled chemokine receptor alone is still unclear. Since this chemokine receptor is engaged and activated in lymphocytes by GPCRs, it is possible that these Gq-coupled receptors may interact functionally with Gi to regulate chemotaxis in lymphocytes during the effector stage [42].

2.3. Others

AT(1)R, one of the best-studied GPCRs, signals through Gq to transduce signals on lymphocytes in autoimmune-regulated cardiomyopathy and hypertension [43]. Experimental findings support the concept that the balance between T cell-induced inflammation and T cell suppressor responses is critical for the regulation of blood pressure levels; autoantibodies to these receptors can exacerbate the pathological process [44]. High levels of autoantibodies against the second extracellular loop of α1-adrenoceptor (α1-AR) are also found in patients with hypertension, suggesting an important role of α1-AR and AT(1)R autoimmunity in the pathogenesis and management of hypertension, particularly in patients having high levels of receptor-associated autoantibodies [11, 45, 46]. However, the precise mechanism is still unknown.

3. How Do Gq-Coupled Receptors Play a Role in Autoimmunity?

Autoimmunity comprises a variety of autoreactive lymphocytes characterized by the loss of tolerance to a variety of autoantigens and imbalanced humoral and cellular immunity in biological systems [19, 23, 47]. Gq-coupled GPCRs on different lymphocytes can transduce a series of extracellular signals into the nucleus to regulate immune function. Immune responses are coordinated by the extracellular ligand to GPCR on lymphocytes, and activated intracellular Gq protein then activates enzymes, second messengers, protein kinases, and nuclear translocation, consequently inducing the migration, activation, and apoptosis of lymphocytes [48]. This well-orchestrated function of hematopoietic cells is complex; however, it is clear that Gq-coupled receptors and the signaling molecules that reside downstream of these receptors are critical to these functions.

3.1. Induction of T-Cell Proliferation by GqPCR

3.1.1. GnRHR

Women are more likely to actively express GnRH and GnRHR than men, as described above, particularly during the reproductive period, at which time immune responses are different [26, 30]. Furthermore, in the spleen and thymus, the expression of G proteins on mononuclear cells differs in a gender-dependent manner [23]. GnRHR exhibits direct immunostimulatory properties, and lymphocytes produce GnRH and express GnRHR [23, 26, 49]. The G protein Gαq/11 regulates the transduction of signals from multiple hormones from specific cell surface receptors to a variety of intracellular effectors, including the AC pathway, PLC-β, and the ion channel pathway [49]. Jacobson et al. [26] demonstrated that antisense nucleotides to Gαq/11 inhibit hormone and GnRHR signaling, suppressing the proliferation of T cells from female mice after in vitro culture. Additional studies have shown that antisense oligonucleotides to Gq-coupled GPCRs can also be effective in vivo for ameliorating murine lupus; specifically, antisense oligonucleotides directed against Gαq in female lupus-prone mice effectively reduce serum IgG levels, anti-DNA antibody levels, hematuria, and proteinuria, even in terms of the histopathology of renal biopsies [27]. Thus, these studies demonstrate the utility of GnRH inhibitors to modulate GqPCR activation in mice and suggest a novel potential target for the treatment of lupus.

3.1.2. Chemokine Receptors

Molon et al. [48] have shown that signals mediated by chemokine receptors may compete with T-cell receptor stop signals and determine the duration of T-cell antigen-presenting cell interactions. During T-cell stimulation by antigen-presenting cells, T-cell chemokine receptors coupled to Gq and/or G11 protein are recruited to the immunological synapse. When chemokine receptors are sequestered at the immunological synapse, T cells become insensitive to chemotactic gradients, form more stable conjugates, and enhance proliferation and cytokine production. Thus, chemokine receptor trapping at the immunological synapse enhances T-cell activation by improving T-cell antigen-presenting cell attractions and impeding the “distraction” of successfully engaged T cells by other chemokine sources. Ngai et al. [15] suggested that optimal activation of the T-cell receptor requires signaling through chemokine receptor-Gq and that removal of Gαq locks cells into a migratory phenotype, making the cell less responsive to T-cell receptor signaling. Previous studies have shown that activation of Gαq inhibits migration through an Lck-SHP-1 pathway, priming cells for activation through the T-cell receptor-CD3 complex [42]. Thus, these novel GqPCR signaling pathways are involved in mediating the threshold of chemotaxis and T-cell receptor activation, playing an irreplaceable role in immunity and autoimmunity.

3.2. Induction of DC and Monocyte Migration by GqPCRs

A Gi-coupled classic pathway activates T lymphocytes and alternative Gq-dependent chemokine receptors, promoting the migration of DCs and monocytes. Furthermore, Gq, similar to CD38, regulates extracellular calcium entry in chemokine-stimulated cells. Gq-deficient (Gnaq−/−) DCs and monocytes are unable to migrate to inflammatory sites and lymph nodes in vivo, demonstrating that this alternative Gq-coupled chemokine receptor signaling pathway is critical for the initiation of immune responses [32, 38].

4. The Diversity of Gq-Coupled GPCRs Mediates Activation of Signal-Regulated Pathways

Binding partners to GqPCR distinct from PLC-β include novel activators (Ric-8A and tubulin), candidate effectors (RhoGEFs, PI3K, GPCR kinases (GRKs), Btk, and complex regulator of G-protein signaling (RGS) proteins), regulators (RGS proteins and GRKs), and scaffold/adaptor proteins (EBP50/NHERF1, CDP/CD81, caveolin-1, and TPR1) [1, 4, 6, 50]. Downstream of these signaling proteins, signals through GPCR to Gq family members exhibit unexpected differences in signaling pathways and the regulation of gene expression profiles [8, 50].

4.1. Gq-Related PLC-β and PKC/Calcium Pathways

PLC-β is the most well-known downstream effector molecule of GqPCR (Figure 1). The canonical pathway for the Gq/11 family is the activation of PLC-β enzymes, which catalyze the hydrolysis of the minor membrane phospholipid phosphatidylinositol bisphosphate (PIP2) to release IP3 and DAG [4–7, 13, 14]. These second messengers serve to propagate and amplify the GqPCR-mediated signal with calcium mobilization following release from IP3-regulated intracellular stores and DAG-mediated stimulation of PKC activity [4, 5]. Inositol lipids, DAG, PKC, and calcium each participate in multiple signaling networks, linking Gq family members through a host of different cellular events [1]. This pathway has been widely studied as a marker of GqPCR signaling [8]. As the aforementioned chemokine receptors, there are classic (Gi) and alternative (Gq) coupled GPCR pathways depending on the specific type of the chemokines and chemokine-stimulated cells [38]. The Gi is through AC pathway mentioned in the introduction part. The Gq activates the PLC family that can regulate the extracellular calcium entry in chemokine-stimulated cell and also subsequently influence the downstream effectors such as PI3K/Akt for survival of the cell.

Figure 1

Signaling pathways demonstrating the link between Gq-coupled receptors and induction of autoimmunity. The figure shows the major signaling pathways that are believed to regulate the extracellular signals transduce into lymphocytes, which include the classic PLC-β/PKC pathway (left) and inhibition of the PI3K-Akt pathway to maintain normal immune tolerance (right) while Gq can also facilitate the activation of the ERK-MAPK pathway, regulating the differentiation of lymphocytes and controlling the expression of cytokines (middle).

4.2. The PI3K-Akt-Mammalian Target of Rapamycin (mTOR) Pathway

Multiple reports have documented the negative influence of Gq-coupled receptors on the growth factor-directed activation of PI3K and Akt isoforms [1, 4–7, 13]. One report showed that Gαq directly inhibits the PI3K p110a catalytic subunit in vitro [51]. In addition, a previous study also showed that Gαq represses Akt activation in fibroblast cell lines [52–54] and cardiomyocytes [55, 56]; however, overexpression of Gαq in cardiomyocytes leads to cardiac hypertrophy and cardiomyocyte apoptosis [10, 57].

PI3K can be activated by the βγ dimers released from Gi-coupled receptors [5]. In contrast, Gq normally inhibits PI3K activation and prevents activation of Akt [6, 7, 10, 14, 38]. Furthermore, Gαq inhibits the activation of the PI3K-Akt pathway, as has been demonstrated in Gnαq−/− mice. Indeed, by measurement of the phosphorylation of Akt at Ser473 (phospho-Akt), a phosphorylation site under the control of PI3K demonstrated that the level of phospho-Akt was higher in Gnαq−/− mice than in WT B cells [58]. Furthermore, deletion of phosphatase and tensin homolog (PTEN), an inhibitor of PI3K, also promotes mature B-cell survival [59] and can rescue autoreactive B cells from anergy [60]. Interestingly, the autoreactive prone marine zone-like B (MZB) cell compartment is also expanded in mice expressing activated p110 or lacking PTEN [61]. In the absence of Gαq, B cells constitutively express higher levels of activated Akt and preferentially survive BCR-induced cell death signals and BAFF (B-cell-activating factor of the TNF family, also known as BLyS, for B lymphocyte stimulator) withdrawal in vitro and in vivo [10, 58, 62]. The B cells isolated from multiple models of autoimmunity have been reported to express elevated levels of phospho-Akt [62], and perturbations in the PI3K/Akt axis can lead to the development of autoimmunity [51, 62].

4.3. The MAPK/ERK Pathway

In addition to PLC-β and PI3K, many studies have demonstrated that Gq-coupled receptors can also regulate other intracellular signaling molecules, such as members of the MAPK family [6, 7, 50, 57]. The MAPK signaling cascade is one of the most ancient and evolutionarily conserved signaling pathways and responds to a broad range of extracellular and intracellular changes [63–67]. Among the MAPKs, p38 MAPK regulates the expression of tumor necrosis factor- (TNF-) α, interferon- (IFN-) γ, and other cytokines via transcriptional and posttranscriptional mechanisms. Therefore, inhibiting p38 MAPK may abrogate TNF-α, providing potential anti-inflammatory effects [65, 68, 69]. Predominant Th1 and Th17 cytokine production are characteristic of many organ-specific autoimmune diseases, and the dysregulation of p38 MAPK activity specifically in autoreactive lymphocytes appears to enhance IL-17 and IFN-γ expression [66, 70–72]. Additionally, the ERK pathway can be activated by the small G protein Ras via the Raf group of MAP kinase kinase kinases (MKKKs) [66]. Solid evidence has supported that endothelin-dependent ERK/MAPK activation depends on the GqPCR/PLC-β/Ca²⁺/Src signaling cascade [64]. Taken together, these studies have shown that GqPCR and Gαq are involved in the activation of ERK.

Thus, complex GPCR signaling should be studied as a concerted network at the systems level [73]. The detailed “cross-talk” mechanism between these GqPCR pathways still needs to be explored in the future.

5. Perspectives

In this review, we have outlined current evidence supporting the biological, pathological, and cell signaling functions of Gq-coupled GPCRs in autoimmunity. This discussion reinforced the idea of cell signaling diversity and challenged the established paradigm that Gq-coupled GPCR signals in immunology are functionally redundant. Moreover, studies of traditional pathways alone do not account for many Gq-mediated responses; Gαq-linked signaling suggests that GqPCRs have complex roles in signal transduction that are not yet fully understood.

Our previous studies have shown that Gq is associated with immune diseases and has pivotal roles in autoimmunity [17, 18, 24, 33, 38, 72, 74]. Gq is downregulated in RA’s patients and relates to the disease’s activity [74]; it can control the RA’s progress via Th17 differentiation [72]. While Gq-containing G proteins can regulate B-cell selection and survival and are required to prevent B-cell-dependent autoimmunity [38], the deficiency of Gq can enhance the T-cell’s survival [17] and influence the migration of DCs and neutrophils. Based on our unpublished data it is also related to autoinflammatory diseases. Therefore, we are interested in clarifying the role of Gq-coupled GPCRs in immune tolerance and autoimmunity, with the aim of improving therapeutic approached. Nonetheless, there are still some limitations to the available data describing the role of Gq-coupled GPCRs in autoreactive lymphocytes. Further studies using in vitro-derived lymphocytes may not accurately reflect the situations occurring in vivo. Moreover, the aforementioned studies involved different races and small patient populations, which may also have influenced the final results.

To date, many studies have focused on Gq-coupled membrane receptors and, to a lesser extent, G11. However, relatively little is known about G14 and G15/16. Future studies of autoimmunity may improve our understanding of the unique cell signaling roles and properties of other Gq/11 family proteins, including G14 and G15/16. Taken together, our discussion herein summarizes our current understanding of the complexity of Gq-coupled membrane receptor signaling and highlights many exciting new areas for future investigations in autoimmunity.

Conflict of Interests

The authors declare no conflict of interests.

Acknowledgment

The authors would like to acknowledge financial support from the Natural Science Foundation of China (Grant no. 81471534) to Dr. Guixiu Shi.

References

K. B. Hubbard and J. R. Hepler, “Cell signalling diversity of the Gqα family of heterotrimeric G proteins,” Cellular Signalling, vol. 18, no. 2, pp. 135–150, 2006.
View at: Publisher Site | Google Scholar
Z. Naor, “Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor,” Frontiers in Neuroendocrinology, vol. 30, no. 1, pp. 10–29, 2009.
View at: Publisher Site | Google Scholar
K. Sisley, R. Doherty, and N. A. Cross, “What hope for the future? GNAQ and uveal melanoma,” The British Journal of Ophthalmology, vol. 95, no. 5, pp. 620–623, 2011.
View at: Publisher Site | Google Scholar
S. R. Neves, P. T. Ram, and R. Iyengar, “G protein pathways,” Science, vol. 296, no. 5573, pp. 1636–1639, 2002.
View at: Publisher Site | Google Scholar
N. Wettschureck, A. Moers, and S. Offermanns, “Mouse models to study G-protein-mediated signaling,” Pharmacology & Therapeutics, vol. 101, no. 1, pp. 75–89, 2004.
View at: Publisher Site | Google Scholar
N. Mizuno and H. Itoh, “Functions and regulatory mechanisms of Gq-signaling pathways,” Neuro-Signals, vol. 17, no. 1, pp. 42–54, 2009.
View at: Publisher Site | Google Scholar
G. Sánchez-Fernández, S. Cabezudo, C. García-Hoz et al., “Gαq signalling: the new and the old,” Cellular Signalling, vol. 26, no. 5, pp. 833–848, 2014.
View at: Publisher Site | Google Scholar
T. Kawakami and W. Xiao, “Phospholipase C-β in immune cells,” Advances in Biological Regulation, vol. 53, no. 3, pp. 249–257, 2013.
View at: Publisher Site | Google Scholar
A. M. Lyon, V. G. Taylor, and J. J. G. Tesmer, “Strike a pose: Gαq complexes at the membrane,” Trends in Pharmacological Sciences, vol. 35, no. 1, pp. 23–30, 2014.
View at: Publisher Site | Google Scholar
S. Mishra, H. Ling, M. Grimm, T. Zhang, D. M. Bers, and J. H. Brown, “Cardiac hypertrophy and heart failure development through Gq and CaM kinase II signaling,” Journal of Cardiovascular Pharmacology, vol. 56, no. 6, pp. 598–603, 2010.
View at: Publisher Site | Google Scholar
A. Fišerová, M. Starec, M. Kuldová et al., “Effects of D2-dopamine and α-adrenoceptor antagonists in stress induced changes on immune responsiveness of mice,” Journal of Neuroimmunology, vol. 130, no. 1-2, pp. 55–65, 2002.
View at: Publisher Site | Google Scholar
S.-M. Lee, Y. Yang, and R. B. Mailman, “Dopamine D1receptor signaling: Does GαQ-phospholipase C actually play a role?” The Journal of Pharmacology and Experimental Therapeutics, vol. 351, no. 1, pp. 9–17, 2014.
View at: Publisher Site | Google Scholar
B. A. Wilson and M. Ho, “Pasteurella multocida toxin as a tool for studying Gq signal transduction,” Reviews of Physiology, Biochemistry and Pharmacology, vol. 152, pp. 93–109, 2004.
View at: Publisher Site | Google Scholar
R. S. Misra, G. Shi, M. E. Moreno-Garcia et al., “Gαq-containing G proteins regulate B cell selection and survival and are required to prevent B cell–dependent autoimmunity,” Journal of Experimental Medicine, vol. 207, no. 8, pp. 1775–1789, 2010.
View at: Publisher Site | Google Scholar
J. Ngai, T. Methi, K. W. Andressen et al., “The heterotrimeric G-protein α-subunit Gαq regulates TCR-mediated immune responses through an Lck-dependent pathway,” European Journal of Immunology, vol. 38, no. 11, pp. 3208–3218, 2008.
View at: Publisher Site | Google Scholar
L. Svensson, P. Stanley, F. Willenbrock, and N. Hogg, “The Galphaq/11 proteins contribute to T lymphocyte migration by promoting turnover of integrin LFA-1 through recycling,” PLoS ONE, vol. 7, no. 6, Article ID e38517, 2012.
View at: Publisher Site | Google Scholar
D. Wang, Y. Zhang, Y. He, Y. Li, F. E. Lund, and G. Shi, “The deficiency of Gαq leads to enhanced T-cell survival,” Immunology and Cell Biology, vol. 92, no. 9, pp. 781–790, 2014.
View at: Publisher Site | Google Scholar
Y. Wang, Y. Li, and G. Shi, “The regulating function of heterotrimeric G proteins in the immune system,” Archivum Immunologiae et Therapiae Experimentalis, vol. 61, no. 4, pp. 309–319, 2013.
View at: Publisher Site | Google Scholar
A. Antonelli, S. M. Ferrari, D. Giuggioli, E. Ferrannini, C. Ferri, and P. Fallahi, “Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases,” Autoimmunity Reviews, vol. 13, no. 3, pp. 272–280, 2014.
View at: Publisher Site | Google Scholar
C. Carvalho, S. L. Calvisi, B. Leal et al., “CCR5-Delta32: implications in SLE development,” International Journal of Immunogenetics, vol. 41, no. 3, pp. 236–241, 2014.
View at: Publisher Site | Google Scholar
J. Y. Choi, J. H. Ho, S. G. Pasoto et al., “Circulating follicular helper-like T cells in systemic lupus erythematosus: association with disease activity,” Arthritis & Rheumatology, vol. 67, no. 4, pp. 988–999, 2015.
View at: Publisher Site | Google Scholar
G. S. Firestein, “Evolving concepts of rheumatoid arthritis,” Nature, vol. 423, no. 6937, pp. 356–361, 2003.
View at: Publisher Site | Google Scholar
J. D. Jacobson, “Gonadotropin-releasing hormone and G proteins: potential roles in autoimmunity,” Annals of the New York Academy of Sciences, vol. 917, pp. 809–818, 2000.
View at: Google Scholar
Y. Li, Y. Wang, Y. He et al., “Gαq gene promoter polymorphisms and rheumatoid arthritis in the Han Chinese population are not associated,” Genetics and Molecular Research, vol. 12, no. 2, pp. 1841–1848, 2013.
View at: Publisher Site | Google Scholar
D. Stanislaus, J. H. Pinter, J. A. Janovick, and P. M. Conn, “Mechanisms mediating multiple physiological responses to gonadotropin-releasing hormone,” Molecular and Cellular Endocrinology, vol. 144, no. 1-2, pp. 1–10, 1998.
View at: Publisher Site | Google Scholar
J. D. Jacobson, M. A. Ansari, M. Kinealy, and V. Muthukrishnan, “Gender-specific exacerbation of murine lupus by gonadotropin-releasing hormone: potential role of Gα(q/11),” Endocrinology, vol. 140, no. 8, pp. 3429–3437, 1999.
View at: Google Scholar
M. A. Ansari, M. Dhar, V. Muthukrishnan, T. L. Morton, N. Bakht, and J. D. Jacobson, “Administration of antisense oligonucleotides to ${G α}_{Q / 11}$ reduces the severity of murine lupus,” Biochimie, vol. 85, no. 6, pp. 627–632, 2003.
View at: Publisher Site | Google Scholar
J. D. Jacobson, L. J. Crofford, L. Sun, and R. L. Wilder, “Cyclical expression of GnRH and GnRH receptor mRNA in lymphoid organs,” Neuroendocrinology, vol. 67, no. 2, pp. 117–125, 1998.
View at: Publisher Site | Google Scholar
T. L. Morton, M. A. Ansari, and J. D. Jacobson, “Gender differences and hormonal modulation of G proteins G $α_{q / 11}$ expression in lymphoid organs,” Neuroendocrinology, vol. 78, no. 3, pp. 147–153, 2003.
View at: Publisher Site | Google Scholar
P. E. Micevych, J. Kuo, and A. Christensen, “Physiology of membrane oestrogen receptor signalling in reproduction,” Journal of Neuroendocrinology, vol. 21, no. 4, pp. 249–256, 2009.
View at: Publisher Site | Google Scholar
V. Rider and N. I. Abdou, “Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus,” International Immunopharmacology, vol. 1, no. 6, pp. 1009–1024, 2001.
View at: Publisher Site | Google Scholar
H. Arai and I. F. Charo, “Differential regulation of G-protein-mediated signaling by chemokine receptors,” The Journal of Biological Chemistry, vol. 271, no. 36, pp. 21814–21819, 1996.
View at: Publisher Site | Google Scholar
Y. Liu and G. Shi, “Role of G protein-coupled receptors in control of dendritic cell migration,” BioMed Research International, vol. 2014, Article ID 738253, 11 pages, 2014.
View at: Publisher Site | Google Scholar
C. A. Flanagan, “Receptor conformation and constitutive activity in CCR5 chemokine receptor function and HIV infection,” Advances in Pharmacology, vol. 70, pp. 215–263, 2014.
View at: Publisher Site | Google Scholar
M. Henneken, T. Dörner, G.-R. Burmester, and C. Berek, “Differential expression of chemokine receptors on peripheral blood B cells from patients with rheumatoid arthritis and systemic lupus erythematosus,” Arthritis Research & Therapy, vol. 7, no. 5, pp. R1001–R1013, 2005.
View at: Publisher Site | Google Scholar
O. Launay, S. Paul, A. Servettaz et al., “Control of humoral immunity and auto-immunity by the CXCR4/CXCL12 axis in lupus patients following influenza vaccine,” Vaccine, vol. 31, no. 35, pp. 3492–3501, 2013.
View at: Publisher Site | Google Scholar
C. K. Wong, P. T. Y. Wong, L. S. Tam, E. K. Li, D. P. Chen, and C. W. K. Lam, “Elevated production of B Cell Chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity,” Journal of Clinical Immunology, vol. 30, no. 1, pp. 45–52, 2010.
View at: Publisher Site | Google Scholar
G. Shi, S. Partida-Sánchez, R. S. Misra et al., “Identification of an alternative Gαq-dependent chemokine receptor signal transduction pathway in dendritic cells and granulocytes,” The Journal of Experimental Medicine, vol. 204, no. 11, pp. 2705–2718, 2007.
View at: Publisher Site | Google Scholar
L. Bidyalaxmi Devi, A. Bhatnagar, A. Wanchu, and A. Sharma, “A study on the association of autoantibodies, chemokine, and its receptor with disease activity in systemic lupus erythematosus in North Indian population,” Rheumatology International, vol. 33, no. 11, pp. 2819–2826, 2013.
View at: Publisher Site | Google Scholar
C. R. Mackay, “Moving targets: cell migration inhibitors as new anti-inflammatory therapies,” Nature Immunology, vol. 9, no. 9, pp. 988–998, 2008.
View at: Publisher Site | Google Scholar
G. Trujillo, A. J. Hartigan, and C. M. Hogaboam, “T regulatory cells and attenuated bleomycin-induced fibrosis in lungs of CCR7^−/− mice,” Fibrogenesis & Tissue Repair, vol. 3, article 18, 2010.
View at: Publisher Site | Google Scholar
J. Ngai, M. Inngjerdingen, T. Berge, and K. Tasken, “Interplay between the heterotrimeric G-protein subunits Galphaq and Galphai2 sets the threshold for chemotaxis and TCR activation,” BMC Immunology, vol. 10, article 27, 2009.
View at: Google Scholar
M. Platten, S. Youssef, E. M. Hur et al., “Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 35, pp. 14948–14953, 2009.
View at: Publisher Site | Google Scholar
B. Rodríguez-Iturbe, H. Pons, Y. Quiroz, and R. J. Johnson, “The immunological basis of hypertension,” American Journal of Hypertension, vol. 27, no. 11, pp. 1327–1337, 2014.
View at: Publisher Site | Google Scholar
S. Nag and S. S. Mokha, “Activation of a Gq-coupled membrane estrogen receptor rapidly attenuates α2-adrenoceptor-induced antinociception via an ERK I/II-dependent, non-genomic mechanism in the female rat,” Neuroscience, vol. 267, pp. 122–134, 2014.
View at: Publisher Site | Google Scholar
L. Yan, X. Tan, W. Chen, H. Zhu, J. Cao, and H. Liu, “Enhanced vasoconstriction to α1 adrenoceptor autoantibody in spontaneously hypertensive rats,” Science China Life Sciences, vol. 57, no. 7, pp. 681–689, 2014.
View at: Publisher Site | Google Scholar
Y. H. Lee, J.-H. Kim, and G. G. Song, “Chemokine receptor 5 Delta32 polymorphism and systemic lupus erythematosus, vasculitis, and primary Sjogren's syndrome. Meta-analysis of possible associations,” Zeitschrift für Rheumatologie, vol. 73, no. 9, pp. 848–855, 2014.
View at: Publisher Site | Google Scholar
B. Molon, G. Gri, M. Bettella et al., “T cell costimulation by chemokine receptors,” Nature Immunology, vol. 6, no. 5, pp. 465–471, 2005.
View at: Publisher Site | Google Scholar
J. P. Hapgood, H. Sadie, W. van Biljon, and K. Ronacher, “Regulation of expression of mammalian gonadotrophin-releasing hormone receptor genes,” Journal of Neuroendocrinology, vol. 17, no. 10, pp. 619–638, 2005.
View at: Publisher Site | Google Scholar
J. H. Kehrl and S. Sinnarajah, “RGS2: a multifunctional regulator of G-protein signaling,” The International Journal of Biochemistry & Cell Biology, vol. 34, no. 5, pp. 432–438, 2002.
View at: Publisher Site | Google Scholar
A. Patke, I. Mecklenbräuker, H. Erdjument-Bromage, P. Tempst, and A. Tarakhovsky, “BAFF controls B cell metabolic fitness through a PKCβ- and Akt-dependent mechanism,” The Journal of Experimental Medicine, vol. 203, no. 11, pp. 2551–2562, 2006.
View at: Publisher Site | Google Scholar
R. K. Bommakanti, S. Vinayak, and W. F. Simonds, “Dual regulation of Akt/protein kinase B by heterotrimeric G protein subunits,” The Journal of Biological Chemistry, vol. 275, no. 49, pp. 38870–38876, 2000.
View at: Publisher Site | Google Scholar
L. M. Ballou, Y.-P. Jiang, G. Du, M. A. Frohman, and R. Z. Lin, “Ca²⁺- and phospholipase D-dependent and -independent pathways activate mTOR signaling,” FEBS Letters, vol. 550, no. 1–3, pp. 51–56, 2003.
View at: Publisher Site | Google Scholar
L. M. Ballou, H.-Y. Lin, G. Fan, Y.-P. Jiang, and R. Z. Lin, “Activated Gαq inhibits p110α phosphatidylinositol 3-kinase and Akt,” The Journal of Biological Chemistry, vol. 278, no. 26, pp. 23472–23479, 2003.
View at: Publisher Site | Google Scholar
A. L. Howes, J. F. Arthur, T. Zhang et al., “Akt-mediated cardiomyocyte survival pathways are compromised by Gαq-induced phosphoinositide 4,5-bisphosphate depletion,” The Journal of Biological Chemistry, vol. 278, no. 41, pp. 40343–40351, 2003.
View at: Publisher Site | Google Scholar
M. R. Morissette, A. L. Howes, T. Zhang, and J. H. Brown, “Upregulation of GLUT1 expression is necessary for hypertrophy and survival of neonatal rat cardiomyocytes,” Journal of Molecular and Cellular Cardiology, vol. 35, no. 10, pp. 1217–1227, 2003.
View at: Publisher Site | Google Scholar
J. S. Gutkind and S. Offermanns, “A new G_q-initiated MAPK signaling pathway in the heart,” Developmental Cell, vol. 16, pp. 163–164, 2009.
View at: Publisher Site | Google Scholar
S. L. Pogue, T. Kurosaki, J. Bolen, and R. Herbst, “B cell antigen receptor-induced activation of Akt promotes B cell survival and is dependent on Syk kinase,” Journal of Immunology, vol. 165, no. 3, pp. 1300–1306, 2000.
View at: Publisher Site | Google Scholar
R. Kumar, S. Srinivasan, S. Koduru et al., “Psoralidin, an herbal molecule, inhibits phosphatidylinositol 3-kinase-mediated Akt signaling in androgen-independent prostate cancer cells,” Cancer Prevention Research, vol. 2, no. 3, pp. 234–243, 2009.
View at: Publisher Site | Google Scholar
C. D. Browne, C. J. Del Nagro, M. H. Cato, H. S. Dengler, and R. C. Rickert, “Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy,” Immunity, vol. 31, no. 5, pp. 749–760, 2009.
View at: Publisher Site | Google Scholar
A. N. Anzelon, H. Wu, and R. C. Rickert, “Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function,” Nature Immunology, vol. 4, no. 3, pp. 287–294, 2003.
View at: Publisher Site | Google Scholar
T. Wu and C. Mohan, “The AKT axis as a therapeutic target in autoimmune diseases,” Endocrine, Metabolic & Immune Disorders Drug Targets, vol. 9, no. 2, pp. 145–150, 2009.
View at: Publisher Site | Google Scholar
J.-Y. Choe, S.-J. Lee, S.-H. Park, and S.-K. Kim, “Tacrolimus (FK506) inhibits interleukin-1β-induced angiopoietin-1, Tie-2 receptor, and vascular endothelial growth factor through down-regulation of JNK and p38 pathway in human rheumatoid fibroblast-like synoviocytes,” Joint Bone Spine, vol. 79, no. 2, pp. 137–143, 2012.
View at: Publisher Site | Google Scholar
H. Cramer, K. Schmenger, K. Heinrich et al., “Coupling of endothelin receptors to the ERK/MAP kinase pathway. Roles of palmitoylation and Gα_q,” The FEBS Journal, vol. 268, no. 20, pp. 5449–5459, 2001.
View at: Publisher Site | Google Scholar
G. Cui, X. Qin, Y. Zhang, Z. Gong, B. Ge, and Y. Q. Zang, “Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice,” The Journal of Biological Chemistry, vol. 284, no. 41, pp. 28420–28429, 2009.
View at: Publisher Site | Google Scholar
C. Dong, R. J. Davis, and R. A. Flavell, “MAP kinases in the immune response,” Annual Review of Immunology, vol. 20, pp. 55–72, 2002.
View at: Publisher Site | Google Scholar
D. M. Fuller, M. Zhu, S. Koonpaew, M. I. Nelson, and W. Zhang, “The importance of the erk pathway in the development of linker for activation of T cells-mediated autoimmunity,” Journal of Immunology, vol. 189, no. 8, pp. 4005–4013, 2012.
View at: Publisher Site | Google Scholar
A. Mavropoulos, T. Orfanidou, C. Liaskos et al., “p38 Mitogen-activated protein kinase (p38 MAPK)-mediated autoimmunity: lessons to learn from ANCA vasculitis and pemphigus vulgaris,” Autoimmunity Reviews, vol. 12, no. 5, pp. 580–590, 2013.
View at: Publisher Site | Google Scholar
A. Mavropoulos, T. Orfanidou, C. Liaskos et al., “P38 MAPK signaling in pemphigus: implications for skin autoimmunity,” Autoimmune Diseases, vol. 2013, Article ID 728529, 11 pages, 2013.
View at: Publisher Site | Google Scholar
R. Noubade, D. N. Krementsov, R. Del Rio et al., “Activation of p38 MAPK in CD4 T cells controls IL-17 production and autoimmune encephalomyelitis,” Blood, vol. 118, no. 12, pp. 3290–3300, 2011.
View at: Publisher Site | Google Scholar
R. Wei, L. Dong, Q. Xiao, D. Sun, X. Li, and H. Nian, “Engagement of Toll-like receptor 2 enhances interleukin (IL)-17⁺ autoreactive T cell responses via p38 mitogen-activated protein kinase signalling in dendritic cells,” Clinical and Experimental Immunology, vol. 178, no. 2, pp. 353–363, 2014.
View at: Publisher Site | Google Scholar
Y. Liu, D. Wang, F. Li, and G. Shi, “Gαq controls rheumatoid arthritis via regulation of Th17 differentiation,” Immunology and Cell Biology, vol. 93, no. 7, pp. 616–624, 2015.
View at: Publisher Site | Google Scholar
M. E. Csete and J. C. Doyle, “Reverse engineering of biological complexity,” Science, vol. 295, no. 5560, pp. 1664–1669, 2002.
View at: Publisher Site | Google Scholar
Y. Wang, Y. Li, Y. He et al., “Expression of G protein αq subunit is decreased in lymphocytes from patients with rheumatoid arthritis and is correlated with disease activity,” Scandinavian Journal of Immunology, vol. 75, no. 2, pp. 203–209, 2012.
View at: Publisher Site | Google Scholar

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Copyright © 2016 Lu Zhang and Guixiu Shi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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