Gαq and Gα11 contribute to the maintenance of cellular electrophysiology and Ca2+ handling in ventricular cardiomyocytes

AIMS: Gα(q) and Gα(11) signalling pathways contribute to cardiac diseases such as hypertrophy and arrhythmia, but their role in cardiac myocytes from healthy hearts has remained unclear. We aimed to investigate the contribution of Gα(q) and Gα(11) signalling to the basal properties of ventricular myocytes. METHODS AND RESULTS: We created a conditional Gα(q) knockout (KO) after tamoxifen injection into gnaq(flox/flox) gna11(-/-) α-MHC Cre(tg/0) mice and found alterations in the electrophysiological and Ca(2+) handling properties of ventricular myocytes using patch-clamp and Fura-2 video imaging. To reveal the genuine effects of protein KO, we investigated the individual contributions of (i) tamoxifen injection, (ii) Cre recombinase expression, (iii) Gα(11) KO, and (iv) Gα(q) KO. Profound and persistent alterations in myocyte properties occurred following the tamoxifen injection alone. Consequently, we used the presence or absence of Cre recombinase expression as the determinant for the Gα(q) KO. Myocytes from the Gα(q) and/or Gα(11) KO mice displayed genuine alterations in the action potentials, membrane capacitance, membrane currents, and Ca(2+) handling (amplitude, post-rest behaviour, and Ca(2+) removal processes). CONCLUSIONS: We conclude that, in a transgenic model, the role of Gα(q) can be best studied using Cre recombinase expression as the molecular determinant for Gα(q) KO rather than tamoxifen/miglyol injection. While excessive hormonal stimulation of the Gα(q)/Gα(11) signalling pathways plays an essential role in cardiac diseases, we propose that the persistent low-level stimulation of these pathways by Gα(q)/Gα(11) activation is instrumental in the physiological behaviour of ventricular myocytes.