A novel functional haplotype in the human GNAS gene alters Galphas expression, responsiveness to beta-adrenoceptor
Ulrich H Frey1, Michael Adamzik, Eva Kottenberg-Assenmacher
1Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, D-45122 Essen, Germany. ulrich.frey@uk-essen.de
Aims:
Cardiac overexpression of the beta-adrenoceptor-coupled G-protein subunit Galphas in mice enhances inotropic responses to sympathetic stimulation, but evokes cardiomyopathy with increasing age. We tested whether functional single nucleotide polymorphisms (SNPs) in the human Galphas (GNAS) gene modulate Galphas expression and assessed functional consequences.
Methods And Results:
Sequencing the promoter and intron 1 of GNAS revealed 11 SNPs resulting in three common haplotypes. Haplotype *3 constructs exhibited significantly higher promoter activity than haplotypes *1 and *2, resulting in a more than 50% higher Galphas mRNA expression in homozygous *3 carriers (*3/*3) than in heterozygous (*3/-) and negative *3 (-/-) carriers (P = 0.002). Basal, Galphas- (via NaF and GTP) and isoproterenol-stimulated adenylyl cyclase (AC) activities were also significantly higher in *3/*3 than in *3/- and -/- carriers. In contrast, direct AC activation via forskolin was independent of GNAS haplotypes. Furthermore, haemodynamic measurements in 137 coronary artery bypass patients revealed a higher cardiac index in *3/*3 carriers than in *3/- and -/- carriers (P = 0.025) associated with a lower NYHA functional class (P = 0.040) and serum NT-proBNP concentrations (P = 0.002).
Conclusion:
SNPs in regulatory regions of GNAS impact upon Galphas expression and stimulated cAMP formation in human hearts in vitro and upon cardiac performance in vivo.
More Related Videos
08:16Detection of G Protein-coupled Receptor Expression in Mouse Vagal Afferent Neurons using Multiplex In Situ Hybridization
Published on: September 20, 2021
08:04Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
Related Concept Videos
Genome-wide Association Studies-GWAS
GWAS does not require the identification of the target gene involved in...
Activation and Inactivation of G Proteins
G-Protein Gated Ion Channels
Sensory...
GPCRs Regulate Adenylyl Cylase Activity
Transducer Mechanism: G Protein–Coupled Receptors
GPCRs are also called heptahelical,...
Pharmacogenomics: Identification of New Drug Targets
