Author:

Abstract:

Regulator of G protein signaling 2 (RGS2) is a member of the RGS protein family. This family of proteins is characterized by a RGS domain, which is responsible for a GTPase activatingprotein (GAP) activity towards heterotrimeric G proteins, thereby acceleratingtermination of G protein-mediated signaling. However, RGS2 is also able tointeract with the alpha subunit of the Gs protein and with adenylyl cyclase (AC) directly, thereby inhibiting cAMP production independently from its GAP activity.cAMP acts as a negative regulator of platelet function via protein kinase A-mediated phosphorylation of the IP3 receptor, cytoskeletal proteins and inhibition of thrombin-induced responses. A heterozygous missense mutation in RGS2, G23D, in 3 patients is associated witha platelet Gs hypofunction. We defined the mechanism behind the enhanced inhibitory action of the mutant RGS2 protein on Gs signaling. The mutation results in the alternative use of the 4 different translation initiation sites in the RGS2 mRNA, with an enhanced expression of RGS2 isoforms containing the domain necessary to bind and inhibit AC. Inaddition, carriers of the G23D mutation show enlarged, round platelets with abnormal alpha granules, suggesting a role for RGS2 in megakaryopoiesis. Indeed, rgs2 overexpression in zebrafish leads to increased thrombocyte numbers, further supporting this hypothesis.RGS2 is expressed ubiquitously and therefore it is expected to have a role in diversebiological systems. A role for RGS2 has already been described in adipogenesis, blood pressure regulationand insulin secretion, all important risk factors for development of the metabolic syndrome. Also, a promoter polymorphism in RGS2 , -395 C/G, leading to enhanced RGS2 expression, is associated with the metabolic syndrome in white European men. The metabolic syndrome is associated with T2DM, but we could not show an increased prevalence of the -395 C/G polymorphism in type 2 diabetic patients compared to a control population. Besides theplatelet phenotype, one of the carriers of the G23D gain-of-function mutation in RGS2 shows additional clinical features of Albright HereditaryOsteodystrophy (AHO), namely obesityand shortened fingers. However,we could not show that rgs2 overexpression affects adipogenesis and bone development in early zebrafish development. We can conclude that the regulation of Gs signaling is an important function of RGS2, which might affect several physiological processes for which an accurate regulation of intracellular cAMP levels is important.