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Aim: Impaired heart rate (HR) response to exercise is associated with increased cardiovascular morbidity and mortality. We analyzed whether common variants (rs5443/C825T and rs5442/G814A) in the G-protein β3 subunit (GNB3) gene modulate interindividual variation in β-blocker responses with respect to HR., Materials & Methods: Among 1614 subjects (347 current β-blocker users) of a population-based study, HR during symptom-limited exercise testing was analyzed by multilevel linear regression models adjusted for potential confounders., Results: In β-blocker users, but not in nonusers, HR was attenuated in rs5443 T allele carriers (TC/TT vs CC) with lower adjusted HR over the entire exercise period from rest to peak workload (3.5 bpm; 95% CI: 1.1-5.8; p < 0.01), and during recovery (4.2 bpm; 95% CI: 0.6-7.8; p = 0.02). The genotype-related HR reducing effect at peak exercise varied by up to 7.5 bpm (CC vs TT), more than a third (35.9%) of the total β-blocker effect (20.9 bpm). By contrast, rs5442 had no impact on any HR-related parameter., Conclusion: In this population-based sample, a common GNB3 polymorphism (C825T) was significantly related with response to β-blocker therapy with respect to HR during exercise and HR recovery, respectively. Further prospective studies are needed to confirm these associations and to examine their potential clinical relevance.

Background: Heterotrimeric G proteins are key mediators of signals from membrane receptors-including the thyroid-stimulating hormone (TSH) receptor-to cellular effectors. Gain-of-function mutations in the TSH receptor and the Galpha(S) subunit occur frequently in hyperfunctioning thyroid nodules and differentiated thyroid carcinomas, whereby the T allele of a common polymorphism (825C>T, rs5443) in the G protein beta3 subunit gene (GNB3) is associated with increased G protein-mediated signal transduction and a complex phenotype. The aim of this study was to investigate whether this common polymorphism affects key parameters of thyroid function and morphology and influences the pathogenesis of thyroid diseases in the general population., Methods: The population-based cross-sectional Study of Health in Pomerania is a general health survey with focus on thyroid diseases in northeast Germany, a formerly iodine-deficient area. Data from 3428 subjects (1800 men and 1628 women) were analyzed for an association of the GNB3 genotype with TSH, free triiodothyronine and thyroxine levels, urine iodine and thiocyanate excretion, and thyroid ultrasound morphology including thyroid volume, presence of goiter, and thyroid nodules., Results: There was no association between GNB3 genotype status and the functional or morphological thyroid parameters investigated, neither in crude analyses nor upon multivariable analyses including known confounders of thyroid disorders., Conclusions: Based on the data from this large population-based survey, we conclude that the GNB3 825C>T polymorphism does not affect key parameters of thyroid function and morphology in the general population of a formerly iodine-deficient area.

The T-allele in the GNB3 C825T polymorphism has been associated with increased cell migration, a prerequisite for metastasis. In this study we investigated a potential association of the C825T-allele status and disease progression in patients with transitional cell carcinoma of the bladder (TCC). Genotyping of the GNB3 C825T polymorphism was performed in 389 patients with transitional cell carcinoma of the bladder and in 104 control subjects and clinical follow-up was worked up in 339 patients. Genotype distribution in 389 patients with bladder cancer was comparable to genotype distribution of the control group. There was no association of GNB3 C825T genotype with tumor stage or grade, but follow-up analysis in the subgroup of non-smokers revealed a shorter time to metastasis in 825T-allele carriers compared to individuals homozygous CC. The genotype of the GNB3 C825T polymorphism appears to influence the biological behavior of tumor disease in non-smoking TCC patients.

The aim of this study was the characterization of the human Gbeta4 subunit of heterotrimeric G proteins. Human Gbeta4 is widely expressed. Its gene is located on chromosome 3 with a genomic structure indistinguishable from that of the genes of Gbeta1 to Gbeta3, but entirely different from Gbeta5. In vitro translation co-precipitation analyses revealed that Gbeta4 can form stable dimers with Ggamma1, Ggamma2, Ggamma3, Ggamma4, Ggamma5, Ggamma7, Ggamma10, Ggamma11, Ggamma12, and Ggamma13, dimers which were also able to stimulate phospholipase beta2.

The T-allele of a polymorphism (C825T) in the gene of the G-protein beta3-subunit is associated with a complex phenotype (hypertension, obesity, altered drug responses) and the occurrence of a splice variant termed Gbeta3s which lacks one of the seven WD-domains that compose Gbeta-proteins. Here, we analysed Gbetagamma dimer formation and Galpha activation by Gbeta3s, key functional characteristics of Gbeta-proteins. Cleavage protection assays frequently used to analyse Gbeta1gamma and Gbeta2gamma dimer formation failed for Gbeta3 and Gbeta3s, while in coprecipitation assays, dimerization of Gbeta3 and Gbeta3s with Ggamma5, Ggamma8(c) and Ggamma12 could be demonstrated. Upon expression of Gbeta3s in COS-7 and Sf9 insect cells, binding of GTPgammaS to Galpha-proteins induced by mastoparan-7 and the M(2) muscarinic acetylcholine receptor was facilitated in comparison with cells overexpressing wildtype Gbeta3, as indicated by twofold reduced agonist EC(50) values. Together, these results indicate that Gbeta3s is a biologically active Gbeta-protein that may mediate the enhanced signal transduction observed in cells with the 825T-allele.

A polymorphism (C825T) in the gene of the G-protein Gbeta3 (GNB3) has been the subject of numerous studies which have shown that the 825T-allele is associated with several cardiovascular and metabolic disorders. Furthermore, the T-allele is associated with the occurrence of the splice variant Gbeta3s which has been implicated in the pathogenesis of these disorders. Here, we characterise a novel splice variant of GNB3, termed Gbeta3v, which is generated by alternative splicing of parts from intron 9 as a novel exon 10a. Gbeta proteins belong to the superfamily of propeller proteins composed of seven regular WD-domains. In Gbeta3v, four of these WD-domains are retained but the protein has a novel C terminus. Gbeta3v forms dimers with Ggamma3 and Ggamma12 but these Gbetagamma complexes do not stimulate phospholipase C-beta2. Thus, a physiological role of Gbeta3v remains to be established. Gbeta3v transcripts are detectable in a wide variety of cells and tissues including fibroblasts, B lymphoblasts, retinoblastoma cells, retina, brain, umbilical cord and colon. However, there is no association with an allele of the GNB3 C825T polymorphism, which suggests that Gbeta3v does not contribute to the complex phenotype observed in association with the 825T-allele.

The T-allele of a polymorphism (C825T) in the gene for the G-protein beta 3 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 G beta 3s, a splice variant of GNB3. G beta 3s is predominantly expressed in cells with the 825T-allele. In the present study we describe the identification and characterization of an additional G beta 3 splice variant referred to as G beta 3s2. Its mRNA is expressed in heart, blood cells and tumour tissue, and its expression is also tightly associated with the GNB3 825T-allele. G beta 3s2 is generated by alternative splicing using non-canonical splice sites. G beta subunits belong to the family of propeller proteins and consist of seven regular propeller blades. Transcripts for G beta 3s2 are lacking 129 bp of the coding sequence of the wild-type G beta 3 protein. Thus the predicted structure consists of only six propeller blades, which resembles the structure of G beta 3s. Co-immunoprecipitation analyses indicated that G beta 3s2 dimerizes with different G gamma subunits, e.g. G gamma 5, G gamma 8(C) and G gamma 12. In Sf9 insect cells, expression of G beta 3s2 together with G gamma 12 enhances receptor-stimulated activation of G alpha(i2). Expression of G beta 3s2 in mammalian cells activated the mitogen-activated protein kinase cascade. Together, these results suggest that G beta 3s2 is a biologically active G beta variant which may play a role in the manifestation of the complex phenotype associated with the 825T-allele.

The 825T-allele of the gene GNB3 encoding the G protein beta3 subunit is associated with hypertension and obesity, and identifies individuals highly responsive to diuretic therapy. Gbeta3s, a Gbeta3 protein variant generated by alternative splicing in carriers of the 825T-allele, is linked to increased signal transduction and is a potential cause for the observed pathophysiology. Here, we searched the entire GNB3 gene for additional polymorphisms and analysed their prevalence in Caucasian, black African and Asian populations. We detected six novel single nucleotide polymorphisms which were termed according to their location as G76A, G1906T, G2906A, A3882C, G5177A, and G5249A. Furthermore, we found a CACA-insertion-deletion polymorphism at position 6496. Genotyping and association studies resulted in the definition of two major GNB3 haplotypes, termed 'C-haplotype' (alleles 825C, 3882A, 5249G, 6496CACA-) and 'T-haplotype' (alleles 825T, 3882C, 5249A, 6496CACA+). Molecular modelling studies revealed that the pre-mRNA structures of both haplotypes exhibit marked differences which may account for the alternative splicing predominantly observed with the T-haplotype. The prevalence of these haplotypes in major ethnic populations differs considerably. Furthermore, we detected additional frequent GNB3 polymorphisms. These variants were restricted to one or two major ethnic populations. Our results will aid future studies on population-specific effects of the GNB3 variants on risk and course of frequent diseases, including hypertension, obesity, stroke and myocardial infarction. Furthermore, they will contribute to the understanding of GNB3-related population-specific pharmacogenetic differences in the response to major drugs, as already shown for diuretics and antidepressants.