Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Regulator of G-Protein Signaling 1 (RGS1)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101824

Synonyms

Historical Background

G-protein-coupled receptors (GPCRs) are cell-surface transmembrane proteins that mediate the effects of a broad spectrum of biological signals. GPCRs signal through heterotrimeric G-proteins that are localized on the inner surface of the plasma membrane and that consist of three subunits: α, β, and γ subunits. Four families of Gα subunits can be distinguished based on their function and amino acid homology, and they are termed: Gαs, Gαi, Gαq, and Gα12 (Gilman 1987). Regulator of G-protein signaling (RGS) family proteins are important effectors that mediate the strength and duration of GPCR and act as negative regulators of the GPCR signaling pathways. RGS proteins function as GTPase-activating proteins (GAPs) that accelerate the GTPase activity of Gα subunits, driving G-protein into its inactive GDP-bound form, hence attenuating or turning off GPCR signaling (Watson et al. 1996). RGS proteins are divided into six subfamilies based on the sequence homology within the RGS domain (Zheng et al. 1999; Ross and Wilkie 2000). RGS1 is a member of the RGS family proteins which belongs to the R4 subfamily (Zheng et al. 1999; Ross and Wilkie 2000) and predominantly interacts with Gαi subunits but ineffective against Gαs (Watson et al. 1996). However, some studies have demonstrated that RGS1 can also inhibit signaling via Gαq-coupled receptors (Xu et al. 1999; Ladds et al. 2007). RGS1, originally coined as 1R20 or BL34, is one of the lymphocyte-specific immediate-early response genes (ERGs) that were identified in phorbol 12-myristate 13-acetate (PMA)-activated B-lymphocytes (Murphy and Norton 1990; Hong et al. 1993). High mRNA levels of RGS1 were found in peripheral blood cells (PBCs) of a child with B cell chronic and acute lymphocytic leukemia (Murphy and Norton 1990; Hong et al. 1993). The complementary deoxyribonucleic acid (cDNA) sequence of RGS1 gene was identified as 1R20 on chromosome band 1q31 (Newton et al. 1993). The RGS domain in RGS1 is shown to be highly conserved, with 11 amino acid (aa) changes between mouse and human RGS1 (Reif and Cyster 2000). Sierra and colleagues further reported that the RGS1 gene contains four exons and spans 4.1 kb (Sierra et al. 2002).

This review will discuss (1) the level and site of expression of RGS1 in mouse, rat, and human tissues, (2) its physiological functions, and (3) its possible implications in pathological disorders, such as autoimmune and vascular diseases.

RGS1 Expression

Expression of RGS1 was reported in various peripheral tissues including human, rat, and murine lymphoid tissues (see Table 1). However, RGS1 mRNA signal was not detected in rat brain regions examined by in situ hybridization (Grafstein-Dunn et al. 2001). Larminie and colleagues further confirmed the lack of RGS1 expression in human brain and reported the preferential expression of RGS1 in human lymphocytes and human lung (Larminie et al. 2004). Another study reported a high RGS1 mRNA expression in the murine lymph node, intestine, and spleen (Reif and Cyster 2000). Besides lymphoid tissues, RGS1 was differentially expressed in the human aorta and heart, with a higher expression in aorta. The atria expressed higher levels of RGS1 than in ventricles (Cho et al. 2003). The RGS1 mRNA expression in the peripheral rat, mouse, and human tissues or organs is summarized in Table 1.
Regulator of G-Protein Signaling 1 (RGS1), Table 1

The organ- or tissue-specific patterns and mRNA expression of RGS1 in the peripheral tissues

Organ/tissue

Species

mRNA expression level

Technique

References

Lymphoid tissues

Spleen

Mouse

High

Northern blot

(Reif and Cyster 2000)

Lymph nodes

Mouse

Mouse

High

Northern blot

RT PCR

(Reif and Cyster 2000)

(Moratz et al. 2004)

Tonsil

Human

 

In situ hybridization

(Hong et al. 1993)

Thymus

Mouse

Low

Northern blot

(Reif and Cyster 2000)

Peyer’s patch

Mouse

Mouse

Moderate

Northern blot

RT PCR

(Reif and Cyster 2000)

(Moratz et al. 2004)

Other tissues/organs

Heart

Human

Human

 

Northern blot and RT-PCR

qPCR

(Cho et al. 2003)

(Larminie et al. 2004)

Aorta

Human

High

Northern blot and RT-PCR

(Cho et al. 2003)

Lungs

Human

Rat

Mouse

Human

High

Low

qPCR

Northern blot

Northern blot

Northern blot

(Larminie et al. 2004)

(Grafstein-Dunn et al. 2001)

(Reif and Cyster 2000)

(Hong et al. 1993)

Intestine

Human

Mouse

High

qPCR

Northern blot

(Larminie et al. 2004)

(Reif and Cyster 2000)

Placenta

Human

Rat

Moderate

qPCR

Northern blot

(Larminie et al. 2004)

(Grafstein-Dunn et al. 2001)

Kidney

Human

Moderate

qPCR

(Larminie et al. 2004)

Testis

Human

Moderate

qPCR

(Larminie et al. 2004)

Live

Rat

 

Northern blot

(Grafstein-Dunn et al. 2001)

Skeletal muscle

Rat

Mouse

Moderate

Northern blot

Northern blot

(Grafstein-Dunn et al. 2001)

(Reif and Cyster 2000)

RGS1 gene has been shown to be inducible. Studies showed that RGS1 was present at low levels in resting B lymphocytes (Hong et al. 1993) or in splenic B cells from unchallenged mice (Reif and Cyster 2000). Treatment of B lymphocytes with mitogens (Staphylococcus aureus Cowan strain I (SAC) and/or PMA) for 24 h induced an expression of RGS1 mRNA level (Hong et al. 1993). Reif and Cyster showed that RGS1 mRNA level was rapidly induced to high levels after an in vivo exposure of IgHEL transgenic B cells to Hen egg lysozyme (HEL) Ag (Reif and Cyster 2000). Anergic HEL autoantigen-binding B cells also showed a slight increase in RGS1 expression. The high expression of RGS1 level in spleen from recombination activating gene knockout (RAG−/−) mice without mature B and T lymphocytes implied that a significant amount of the constitutive RGS1 was in non-B or non-T lymphocytes. Consistent with this finding, purified T and B lymphocytes showed intermediate and low RGS1 expression, respectively (Reif and Cyster 2000). Studies showed that RGS1 was induced by lipopolysaccharide (LPS). LPS-induced septic pigs showed an increase in the RGS1 mRNA at the level of the heart (Panetta et al. 1999). RGS1 mRNA expression was modulated by Toll-like receptor (TLR) agonists in murine bone marrow-derived macrophages (BMDMs) and murine macrophage cell line J774 (Riekenberg et al. 2009). The mRNA levels of RGS1 were upregulated after stimulation with TLR2/1 or TLR2/6 lipopeptide (LP) ligand, TLR4/MD2 LPS ligand, TLR9 CpG DNA ligand, as well as TLR3 ligand poly (I:C) (Riekenberg et al. 2009). Tran and his colleagues demonstrated in their recent study that interferon (IFN)-β-1b could induce RGS1 expression in a concentration-dependent manner in human PBMCs including monocytes and T and B lymphocytes (Tran et al. 2010). RGS1 induction was observed at the RNA and protein level and appeared to be strongest in monocytes. The specific induction of RGS1 by IFN-β was dependent upon the IFN receptor activation which suggested a functional link between IFN and chemokine signaling (Tran et al. 2010). Besides the expression and induction of RGS1 in B lymphocytes, RGS1 mRNA was also detected in freshly isolated and in IL-2-activated natural killer (NK) cells (Kveberg et al. 2005). The RGS1 expression in the immune and nonimmune cells is summarized in Table 2.
Regulator of G-Protein Signaling 1 (RGS1), Table 2

The cell-specific patterns and mRNA expression of RGS1 in the immune cells

Cells

Species

Expression

Level of expression

Technique

References

Cardiac myocytes

Rat

mRNA

Low

RT PCR

Northern blot

(Kardestuncer et al. 1998)

Peritoneal cells

Mouse

mRNA

Low

Northern blot

(Reif and Cyster 2000)

Bone marrow cells

Mouse

mRNA

Low

Northern blot

(Reif and Cyster 2000)

White blood cells

Mouse

Mouse

mRNA

mRNA

Low

Northern blot

RT PCR

(Reif and Cyster 2000)

(Moratz et al. 2004)

PBMC

Human

mRNA

 

RT PCR

(Heximer et al. 1997)

Lymphocytes

B lymphocytes

Human

Human

mRNA

mRNA

High

Very low

qPCR

Northern blot

(Larminie et al. 2004)

(Hong et al. 1993)

Natural killer cells

Rat

mRNA

  

(Kveberg et al. 2005)

Monocyte

Human

mRNA

 

RNA analysis

(Denecke et al. 1999)

Protein

 

Western blot

Some studies reported rapid and spontaneous RGS1 changes in mRNA levels in both human and mouse purified human blood mononuclear cells (PBMCs) (Heximer et al. 1997; Reif and Cyster 2000). RGS1 gene displayed low basal mRNA expression level in freshly isolated human PBMCs which increased upon in vitro incubation for 1 day (Heximer et al. 1997). RGS1 expression also increased in response to the protein synthesis inhibitor cycloheximide (Murphy and Norton 1990), the T thymocyte mitogen concanavalin A (ConA), calcium ionophore (ionomycin), and a classical protein kinase C (PKC) activator named 12-O-tetradecanoylphorbol-13-acetate (TPA) (Heximer et al. 1997).

RGS1 Functions

The activity of RGS1 appears to be tightly controlled and highly dependent on tissue distribution and expression. Since RGS1 is highly expressed in immune cells, this suggests a role for RGS1 in immune cell regulation. Chemokine-dependent activation of GPCRs causes the activation of heterotrimeric G-protein subunits resulting in enhanced cell migration and adhesion (Offermanns and Simon 1996). RGS1 impairs Gαi-signaling responses, and silencing of RGS1 enhances responsiveness to chemokines and impairs desensitization in lymphocytes (Han et al. 2006). Many studies identified a role for RGS1 in the control of lymphocyte homeostasis especially in B lymphocytes. RGS1 regulated B cell responses to chemokines by acting on the Gαi subunit (Moratz et al. 2000). In support of this role, a study on RGS1 knockout mice suggested a link between RGS1 expression and B cell migration (Moratz et al. 2000; Han et al. 2005). RGS1 lacking B cells exhibited hypersensitivity to certain chemokines as well as decreased ability to desensitize upon chemokine re-challenges. RGS1 knockout mice exhibited altered B cell development and organization in lymphoid tissues including (1) early and exaggerated germinal cell formation following immunization; (2) abnormal splenic architecture, which is exacerbated after immunization; (3) shrinkage of Peyer’s patch, and (4) improper trafficking of antibody-secreting cells (ASCs) (Moratz et al. 2004). Moreover, the expression of RGS1 in B cell lines drastically impaired their migratory response to chemokines, C-X-C motif chemokine ligand (CXCL) 12 and CXCL13 (Bowman et al. 1998; Moratz et al. 2000; Reif and Cyster 2000). RGS1 desensitized the chemokine (C-C motif) receptor (CCR) 7 and C-X-C motif chemokine receptor (CXCR) 4 that are critical for the localization of T and B cells in lymphoid organs (Caballero-Franco and Kissler 2016). Reif and Cyster suggested that regulated expression of RGS1 plays a role in changing B cell responsiveness to chemokines during the response of B cells to foreign or self-antigens (Reif and Cyster 2000). RGS1 attenuated migration to the lymphoid chemokines stromal cell-derived factor-1 (SDF-1, also called CXCL12), B lymphocyte chemoattractant (BLC, also called CXCL13), and EBV-induced molecule 1 ligand chemokine (ELC, also called chemokine C-C motif ligand (CCL) 19) (Reif and Cyster 2000). These chemokines signal through three different receptors: CXCR4, CXCR5, and CCR7, respectively. Antigen receptor-induced changes in RGS expression may function to regulate B cell responsiveness to lymphoid chemokines and thereby help direct cell-positioning events in lymphoid organs (Reif and Cyster 2000). Similarly, Bowman and colleagues reported that the expression of human RGS1 inhibits the chemoattractant-induced migration and adhesion (Bowman et al. 1998). In addition to the effects on chemotactic responses, RGS1 has been shown to inhibit interleukin (IL)-8-induced activation of extracellular signal-regulated kinase (ERK) in ERK-transfected 293T cells (Druey et al. 1996). In contrast to B cell findings, spleen and lymph node T cells from RGS1 knockout mice showed normal chemotaxis (Moratz et al. 2004). RGS1 was also shown to limit gut T cell responsiveness to the lymphoid-homing CXCL12 and CCL19. This could explain why exaggerated RGS1 expression in human gut T cells contributes to the colitogenic potential of T cells (Gibbons et al. 2011).

RGS1 Pathophysiology

RGS1 has been implicated in the development of pathophysiological conditions that display alterations in signaling from multiple GPCRs. RGS1 has been associated with various diseases including (1) inflammatory diseases such as multiple sclerosis (MS), inflammatory bowel diseases (IBD), and type I diabetes (TID) and (2) vascular diseases such as abdominal aortic aneurysms (AAA) and atherosclerosis.

RGS1 in Inflammatory Diseases

Genome-wide association studies suggested a strong link of RGS1 polymorphisms (SNPs) with the risk of T cell-mediated chronic inflammatory diseases including MS, celiac disease (CD), and T1D (Hunt et al. 2008; Smyth et al. 2008; International Multiple Sclerosis Genetics 2010; Johnson et al. 2010).

MS is a chronic autoimmune demyelinating disease of the central nervous system (CNS). Recently, RGS1 was identified by the International Multiple Sclerosis Genetics Consortium (IMSGC) as a novel MS susceptibility locus (International Multiple Sclerosis Genetics 2010). Mowry and colleagues further reported that RGS1 polymorphisms were associated with tendencies for reduced attack severity (Mowry et al. 2013). Another study suggested that RGS1 may be associated with the age of onset of MS (Jhonson et al. 2010). A search of the Gene Expression Omnibus (GEO) profile database revealed that levels of RGS1 gene expression are higher in MS patients and are induced in response to IFN-β-1a therapy in early treatment on day 1 (reviewed in Lee and Bou Dagher 2016). Tran and colleagues also showed that IFNβ-1b regulates RGS1 proteins in vitro and in vivo (Tran et al. 2010). A single dose of Betaseron (IFNβ-1b), the first approved treatment for MS, induced an increase in RGS1 mRNA expression 4 h after treatment and an increase in RGS1 protein expression 20 h after treatment in MS patients (Tran et al. 2010). Further studies are needed to understand the relationship between IFN-β, GPCRs, and RGS1 protein with regard to control of immune cell surveillance, maturation, migration, and inflammation in MS.

Common relapsing IBDs, Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal (GI) tract whose susceptibility is determined by a combination of environmental and genetic factors (Bouma et al. 2002). Gibbons and his colleagues identified higher RGS1 mRNA levels in human gut T cells than in peripheral blood T cells. This was exaggerated in intestinal inflammation. Elevated RGS1 levels reduced T cell migration from gut to lymphoid-homing chemokines and contributed to the colitogenic potential of T lymphocytes. On the other hand, RGS1 deficiency selectively enhanced such chemotaxis in gut T cells, impaired their colitogenic potential, and ameliorated colitis (Gibbons et al. 2011).

RGS1 in Vascular Diseases

Vascular inflammation is the underlying cause of some cardiovascular diseases, such as atherosclerosis and AAA. Leukocyte recruitment and accumulation leads to vascular inflammation; therefore, the understanding of how chemokine signaling regulates leukocyte trafficking is crucial for the development of novel therapies. Patel and his colleagues identified RGS1 as a novel candidate gene in atherosclerosis and AAA and revealed its role in monocyte-macrophage trafficking that leads to the development of vascular inflammation. In their study, RGS1 was shown to be upregulated in the atherosclerotic plaque and aortic aneurysms. This study also showed that RGS1 knockout enhanced monocyte-macrophage chemotaxis and impaired desensitization. Furthermore, RGS1 deficiency conferred protection from angiotensin II-induced aortic rupture (Patel et al. 2015).

Panetta and colleagues identified RGS1 transcripts in the heart and artery of septic animals. RGS1 RNA was upregulated in the hearts of LPS-induced septic pigs. Data suggested that RGS1 may contribute to the pathophysiological responses observed in sepsis by promoting the activation of intracellular cascades such as mitogen-activated protein (MAP) kinases (Panetta et al. 1999).

Summary

RGS1 protein, which terminates G-protein signaling and regulates lymphocyte trafficking, has the potential to modulate many in vivo signaling functions via specific Gα subtype-linked GPCR pathways. RGS1 is mainly expressed in the lymphoid tissues, lung, and heart and hence plays a pivotal role in regulating chemokine receptor signaling, chemotaxis, and migration of lymphoid cells into and within lymphoid organs. Any change in the RGS1 expression might result in vascular and neuro-inflammation disease as revealed in MS, CD, UC, AAA, and atherosclerosis. The supporting evidence for the participation of RGS1 proteins in a variety of cellular mechanisms as well as their general role in immune system responses provides scope for this protein as novel therapeutic targets. Being a tissue-associated target for biological and clinical investigations, further studies are required to better characterize its role in pathogenesis, hence setting the stage for the development of therapeutic approaches.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Physiology and Pharmacology, College of Veterinary MedicineUniversity of GeorgiaAthensUSA