Identification and characterization of Gbeta3s2, a novel splice variant of the G-protein beta3 subunit

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Abstract
The T-allele of a polymorphism (C825T) in the gene for the G-protein β3 subunit (GNB3) is associated with cardiovascular and metabolic disorders, distinct cellular features and altered drug responses. The molecular mechanisms that give rise to this complex phenotype have been linked to the occurrence of Gβ3s, a splice variant of GNB3. Gβ3s is predominantly expressed in cells with the 825T-allele. In the present study we describe the identification and characterization of an additional Gβ3 splice variant referred to as Gβ3s2. Its mRNA is expressed in heart, blood cells and tumour tissue, and its expression is also tightly associated with the GNB3 825T-allele. Gβ3s2 is generated by alternative splicing using non-canonical splice sites. Gβ subunits belong to the family of propeller proteins and consist of seven regular propeller blades. Transcripts for Gβ3s2 are lacking 129bp of the coding sequence of the wild-type Gβ3 protein. Thus the predicted structure consists of only six propeller blades, which resembles the structure of Gβ3s. Co-immunoprecipitation analyses indicated that Gβ3s2 dimerizes with different Gγ subunits, e.g. Gγ5, Gγ8C and Gγ12. In Sf9 insect cells, expression of Gβ3s2 together with Gγ12 enhances receptor-stimulated activation of Gαi2. Expression of Gβ3s2 in mammalian cells activated the mitogen-activated protein kinase cascade. Together, these results suggest that Gβ3s2 is a biologically active Gβ variant which may play a role in the manifestation of the complex phenotype associated with the 825T-allele.