G-Protein β3-Subunit Polymorphism and Atrial Fibrillation

Abstract

In search for genetic causes of hypertension, Siffert and coworkers[1]have recently identified a single nucleotide polymorphism in a gene encoding for pertussis-toxin (PTX) sensitive G_i-proteins. The authors had noted that a subgroup of patients with “essential hypertension” displayed in their blood platelets high activity of the Na⁺/H⁺exchanger that could be traced back to enhanced signal transduction in this ubiquitously expressed ion transport system. Signal transduction between receptors and effectors was also enhance.d in immortalized cell lines from these individuals and PTX-sensitive G_i-proteins were likely to be involved [2 3]. The altered activity of G_i-proteins was related to a thymine-for-cytosine polymorphism (C825Tpolymorphism) in exon 10 of the gene encoding for the ß3-subunit of the heterotrimeric complexes(GNB3)[3]. The 825T-allele is associated with alternative splicing of exon 9 resulting in an additional Gß3-s-subunit which is shorter by 41 amino acids but more active than the full-size G[33-subunit [3]. Clinically, the 825T-allele was first associated with essential hypertension [3[4][5][6][7][8]though recently several other clinical conditions have also been associated (see table 1). This is not surprising if one considers the central role of heterotrimeric G-proteins in signal transduction. So far, the enhanced activity of the splice variant Gß3-s has been demonstrated mostly in blood cells, i.e. in immortalized lymphoblasts or freshly isolated neutrophils [26 27]. Since the 825T-allele is present in all cells, we have studied the putative association between 825T-allele status and the activity of signal transduction in human atrial myocytes.