The regulators of G-protein signaling (RGS) proteins were initially characterized as inhibitors of signal transduction cascades initiated by G-protein-coupled receptors (GPCR) because of their ability to increase the intrinsic GTPase activity of heterotrimeric G proteins. This GTPase accelerating protein (GAP) activity enhances G protein deactivation and promotes desensitization. However, in addition to this signature trait, emerging data have revealed an expanding network of proteins, lipids, and ions that interact with RGS proteins and confer additional regulatory functions. This review highlights recent advances in our understanding of the physiological functions of one subfamily of RGS proteins with a high degree of homology (B/R4) gleaned from recent studies of knockout mice or cells with reduced RGS expression. We also discuss some of the newly appreciated interactions of RGS proteins with cellular factors that suggest RGS control of several components of G-protein-mediated pathways, as well as a diverse array of non-GPCR-mediated biological responses.

Significance: Pulmonary hypertension is a devastating disorder without any available treatment strategies that satisfactorily promote the survival of patients. The identification of new therapeutic strategies to treat patients with pulmonary hypertension is warranted. Recent Advances: Human studies have provided evidence that there is increased oxidative stress (lipid peroxidation, protein oxidation, DNA oxidation, and the depletion of smallmolecule antioxidants) in patients with pulmonary hypertension. A variety of compounds with antioxidant properties have been shown to have beneficial therapeutic effects in animal models of pulmonary hypertension, possibly supporting the hypothesis that reactive oxygen species (ROS) are involved in the progression of pulmonary hypertension. Thus, understanding the molecular mechanisms of ROS actions could contribute to the development of optimal, antioxidant-based therapy for human pulmonary hypertension. One such mechanism includes action as a second messenger during cell-signaling events, leading to the growth of pulmonary vascular cells and right ventricular cells. Critical Issues: The molecular mechanisms behind promotion of cell signaling for pulmonary vascular cell growth and right ventricular hypertrophy by ROS are not well understood. Evidence suggests that iron-catalyzed protein carbonylation may be involved. Future Directions: Understanding precise mechanisms of ROS actions should be useful for designing preclinical animal experiments and human clinical trials of the use of antioxidants and/or other redox compounds in the treatment of pulmonary hypertension.

BackgroundPulmonary arterial hypertension remains a devastating disease without a cure. The major complication of this disease is the abnormal growth of vascular cells, resulting in pulmonary vascular remodeling. Thus, agents, which affect the remodeled vessels by killing unwanted cells, should improve treatment strategies. The present study reports that antitumor drugs selectively kill vascular cells in remodeled pulmonary vessels in rat models of pulmonary hypertension.Methods and ResultsAfter developing pulmonary vascular remodeling in chronic hypoxia or chronic hypoxia/SU‐5416 models, rats were injected with antitumor drugs including proteasome inhibitors (bortezomib and MG‐132) and daunorubicin. Within 1 to 3 days, these agents reduced the media and intima thickness of remodeled pulmonary vascular walls, but not the thickness of normal pulmonary vessels. These drugs also promoted apoptotic and autophagic death of vascular cells in the remodeled vessels, but not in normal vessels. We provide evidence that the upregulation of annexin A1, leading to GATA4‐dependent downregulation of Bcl‐xL, is a mechanism for specific apoptotic killing, and for the role of parkin in defining specificity of autophagic killing of remodeled vascular cells. The reversal of pulmonary vascular remodeling increased the capacity of vasodilators to reduce pulmonary arterial pressure.ConclusionsThese results suggest that antitumor drugs can specifically kill cells in remodeled pulmonary vascular walls and may be useful for improving the efficacy of current therapeutic strategies to treat pulmonary arterial hypertension.

Mast cells provoke allergic responses through degranulation and release of proinflammatory mediators after antigen crosslinking of the high affinity immunoglobulin E (IgE) receptor (FcεRI). Regulator of G protein Signaling (RGS) proteins negatively control G-protein-coupled receptormediated signaling through GTPase accelerating protein (GAP) activity. Here, we show that Rgs13 inhibits allergic responses by physically interacting with the regulatory p85α subunit of PI3K in mast cells and disrupting its association with an FcεRI-activated scaffold complex. Rgs13 −/− mice exhibited increased IgE-mediated mast cell degranulation and anaphylaxis. Thus, apart from its regulation of GPCRs, Rgs13 inhibits immune receptor-induced signalosome assembly in MCs. Abnormal Rgs13 expression or function may underlie some cases of idiopathic anaphylaxis or disorders of amplified MC activity.MCs lie in close proximity to nerves and blood vessels in organs exposed to constant environmental challenge such as skin and respiratory and gastrointestinal tract mucosae, suggesting a sentinel function in the innate immune response 1 . MCs also provoke allergic diseases such as asthma and anaphylaxis accompanied by high levels of Ag-specific IgE. In allergic individuals, Ag crosslinks IgE bound to FcεRI on MCs, eliciting release of proinflammatory compounds such as histamine and synthesis of leukotrienes and cytokines. Collectively, these mediators initiate type I hypersensitivity reactions characterized by increased vascular permeability, edema, and smooth muscle contraction.FcεRI is a multiunit immune recognition receptor consisting of α, β, and two γ chains. The α subunit binds IgE while the β and γ subunits transduce extracellular signals 2 . FcεRI crosslinking by IgE/Ag induces phosphorylation of immunoreceptor-based tyrosine activation motifs (ITAMs) in the intracellular portion of the β and γ chains by Lyn tyrosine kinase, which attracts Syk kinase to the γ chain. Tyrosine phosphorylation of Syk then propagates the signaling pathway by recruitment and activation of PI(3)K, phospholipase Cγ (PLCγ), and mitogen-activated protein kinase (MAPK). PI(3)K has an essential function in MC homeostasis and allergic responses 3 . Deletion of p110δ, the principal catalytic PI(3)K subunit in BMMCs, significantly impairs Ag-induced degranulation 4 . PI(3)K-mediated activation of PLCγ, which catalyzes formation of inositol-1, 4, 5 trisphosphate (IP3), evokes a rise in intracellular Ca ++ concentration leading to degranulation 5 . to FcεRI, GPCRs catalyze GDP-GTP exchange on the α subunit of a heterotrimeric G protein to activate a variety of effector pathways 10 . Signaling terminates through the intrinsic GTPase activity of the α subunit, which results in conversion of Gα-GTP to Gα-GDP. Gα-GDP binds Gβγ with high affinity, re-constituting the inactive heterotrimer.RGS proteins specify GPCR signaling durability and intensity through GTPase accelerating (GAP) activity on Gα subunits and/or antagonism of Gα-effector interactions, which results...