Heterotrimeric G Protein Signaling in Allergic Inflammation

Niaid Extramural Activities

Investigators

Linked publications & trials

Abstract

Mast cells and T lymphocytes, two cell types integral to development of an allergic response and asthma, express numerous inflammation-generating receptors coupled to heterotrimeric G proteins (GPCRs). The purpose of this study is to understand mechanisms of intracellular G-protein-coupled signal transduction in these cells and subsequent pathways to inflammation. In particular, the project focuses on the control of G protein activity in inflammatory processes by a novel family of regulators of G protein signaling (RGS proteins), which inhibit G alpha subunits by increasing their GTPase activity. G alpha subunits oscillate between GDP- (inactive) and GTP-(active) bound forms. The GTPase accelerating (GAP) activity of RGS proteins limits the time of interaction of active G-alpha and its effectors, resulting in desensitization of GCPR signaling. Despite a growing body of knowledge concerning the biochemical mechanisms of RGS action, almost nothing is known about the physiological role of these proteins in native mammalian systems.RGS4, a GAP expressed highly in mouse brain, heart, and hematopoietic cells, was found also to be expressed in murine mast cells. RGS4 deficient mice are being generated. A novel role of RGS4 in secretory trafficking was identified through an interaction with the protein COPI complex. COPI is a protein multimer thought to be required for maintenance of Golgi structure and formation of some secretory transport carriers. RGS proteins interact with the subunit Beta prime-COP through a conserved dilysine motif and inhibit the normal association of COP1 with Golgi membranes. Both RGS4 and RGS2-transfected cells demonstrated impaired intracellular transport.The physiology of three additional RGS proteins was studied. RGS1 was shown to be expressed highly in germinal center B lymphocytes and to regulate chemotactic responses to the chemokine stromal derived growth factor (SDF1). Transgenic mice overexpressing RGS16 in T lymphocytes were generated. An uncharacterized protein expressed highly in lung tissue, RGS13, was cloned and expressed. RGS13 specific antibodies were generated and characterized. The antibodies were used for immunohistochemistry, which identified RGS13 protein in the bronchial epithelium of allergen-challenged lung tissue.