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 ; these receptors are considered g protein coupled receptors ( gpcrs ) .
it is estimated that more than 800 gpcrs are encoded in the mammalian genome , supporting that gpcrs are common membrane receptors in cells .
heterotrimeric g proteins consist of an -subunit , which binds to and hydrolyzes guanosine-5-triphosphate ( gtp ) , and - and -subunits , which form an indissociable complex .
gpcrs transmit extracellular signals into the cell by binding to and activating different intracellular signaling proteins , termed g proteins ( g , families gi , gs , gq/11 , g12/13 ) or arrestins .
the gq proteins , like all heterotrimeric g proteins , are composed of three subunits : gq , g , and g .
gq - gtp and the g dimer then transmit receptor - generated signals to downstream effector molecules and protein binding partners until the intrinsic gtpase activity of g hydrolyzes gtp to gdp and the inactive subunits reassociate ; 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 .
the gq/11 subfamily , including gq , g11 , g14 , and g15/16 , shares structural similarity , and activation of the  subunit within each protein complex can activate plc- [ 47 ] .
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- isoforms [ 1 , 49 ] .
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 ( 1ar ) , and angiotensin ii type 1 receptor ( at(1)r ) [ 1113 ] . in the field of immunology , chemokine and
these gqpcrs are expressed on lymphocytes and are regulated by their ligands in the immune system [ 1418 ] .
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 [ 1924 ] .
gq is the most commonly studied subclass of the gq/11 subfamily in the field of immunology   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 ) .
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 .
the interaction between gnrh and its cognate type i receptor ( gnrhr ) in the pituitary results in the activation of gq , plc- , phospholipase a2 ( pla2 ) , and phospholipase d ( pld ) . 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 ca mobilization .
further activation of various protein kinase c isoforms ( pkcs ) induces sequential activation of mitogen - activated protein kinases ( mapks )   and promotes nuclear transcription .
gnrhr mrna and protein have been found in the pituitary , lymphocytes , mononuclear cells , and various types of cancer cells .
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 .
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 .
jacobson   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 . in mice given
additional studies have shown that gnrh ( through gqpcr ) stimulates t / b lymphocyte proliferation in vitro in females only .
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 .
rider and abdou   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 .
chemokine receptors are expressed on t cells , b cells , monocytes , macrophages , and dendritic cells .
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 ) [ 1921 , 32 , 3437 ] . 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   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 .
shi and colleagues   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 , 3641 ] . 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 ) .
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 .
at(1)r , one of the best - studied gpcrs , signals through gq to transduce signals on lymphocytes in autoimmune - regulated cardiomyopathy and hypertension .
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 .
high levels of autoantibodies against the second extracellular loop of 1-adrenoceptor ( 1-ar ) are also found in patients with hypertension , suggesting an important role of 1-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 ]
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 .
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 .
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 .
gnrhr exhibits direct immunostimulatory properties , and lymphocytes produce gnrh and express gnrhr [ 23 , 26 , 49 ] .
the g protein gq/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- , and the ion channel pathway .
jacobson et al .   demonstrated that antisense nucleotides to gq/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 gq 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 .
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 .
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
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 .
.   suggested that optimal activation of the t - cell receptor requires signaling through chemokine receptor - gq and that removal of gq locks cells into a migratory phenotype , making the cell less responsive to t - cell receptor signaling .
previous studies have shown that activation of gq inhibits migration through an lck - shp-1 pathway , priming cells for activation through the t - cell receptor - cd3 complex .
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 .
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 ] .
binding partners to gqpcr distinct from plc- 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 ] .
plc- 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- enzymes , which catalyze the hydrolysis of the minor membrane phospholipid phosphatidylinositol bisphosphate ( pip2 ) to release ip3 and dag [ 47 , 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 .
this pathway has been widely studied as a marker of gqpcr signaling . 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 .
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 .
multiple reports have documented the negative influence of gq - coupled receptors on the growth factor - directed activation of pi3k and akt isoforms [ 1 , 47 , 13 ] .
in addition , a previous study also showed that gq represses akt activation in fibroblast cell lines [ 5254 ] and cardiomyocytes [ 55 , 56 ] ; however , overexpression of gq in cardiomyocytes leads to cardiac hypertrophy and cardiomyocyte apoptosis [ 10 , 57 ] .
in contrast , gq normally inhibits pi3k activation and prevents activation of akt [ 6 , 7 , 10 , 14 , 38 ] .
furthermore , gq inhibits the activation of the pi3k - akt pathway , as has been demonstrated in gnq/ 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 gnq/ mice than in wt b cells .
furthermore , deletion of phosphatase and tensin homolog ( pten ) , an inhibitor of pi3k , also promotes mature b - cell survival   and can rescue autoreactive b cells from anergy .
interestingly , the autoreactive prone marine zone - like b ( mzb ) cell compartment is also expanded in mice expressing activated p110 or lacking pten . in the absence of gq ,
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 , and perturbations in the pi3k / akt axis can lead to the development of autoimmunity [ 51 , 62 ] .
in addition to plc- 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 [ 6367 ] . among the mapks , p38 mapk regulates the expression of tumor necrosis factor- ( tnf- )  , interferon- ( ifn- )  , and other cytokines via transcriptional and posttranscriptional mechanisms .
therefore , inhibiting p38 mapk may abrogate tnf- , 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- expression [ 66 , 7072 ] . additionally , the erk pathway can be activated by the small g protein ras via the raf group of map kinase kinase kinases ( mkkks ) .
solid evidence has supported that endothelin - dependent erk / mapk activation depends on the gqpcr / plc-/ca / src signaling cascade .
taken together , these studies have shown that gqpcr and gq are involved in the activation of erk .
thus , complex gpcr signaling should be studied as a concerted network at the systems level .
the detailed  cross - talk  mechanism between these gqpcr pathways still needs to be explored in the future .
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 ; gq - 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 ; it can control the ra 's progress via th17 differentiation .
while gq - containing g proteins can regulate b - cell selection and survival and are required to prevent b - cell - dependent autoimmunity , the deficiency of gq can enhance the t - cell 's survival   and influence the migration of dcs and neutrophils .
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 ,
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 .
 heterotrimeric g proteins can be divided into gi , gs , gq/11 , and g12/13 subfamilies according to their  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 gq , which is considered the functional  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
2. The Diversity of Gq-Coupled Receptors in Autoimmunity
3. How Do Gq-Coupled Receptors Play a Role in Autoimmunity?
4. The Diversity of Gq-Coupled GPCRs Mediates Activation of Signal-Regulated Pathways
5. Perspectives