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.
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.
