The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics

Zuberi Z, Birnbaumer L, Tinker A. The role of inhibitory heterotrimeric G proteins in the control of in vivo heart rate dynamics. Am J Physiol Regul Integr Comp Physiol 295: R1822-R1830, 2008. First published October 1, 2008; doi:10.1152/ajpregu.90625.2008.-Multiple isoforms of inhibitory G alpha-subunits (G alpha(i1,2,3), as well as G alpha(o)) are present within the heart, and their role in modulating pacemaker function remains unresolved. Do inhibitory G alpha-subunits selectively modulate parasympathetic heart rate responses? Published findings using a variety of experimental approaches have implicated roles for G alpha(i2), G alpha(i3), and G alpha(o) in parasympathetic signal transduction. We have compared in vivo different groups of mice with global genetic deletion of Gi(alpha 1)/G alpha(i3), G alpha(i2), and G alpha(o) against littermate controls using implanted ECG telemetry. Significant resting tachycardia was observed in G alpha(-/-)(i2) and G alpha(-/-)(o) mice compared with control and G alpha(-/-)(i1)/G alpha(-/-)(i3) mice (P<0.05). Loss of diurnal heart rate variation was seen exclusively in G alpha(-/-)(o) mice. Using heart rate variability (HRV) analysis, compared with littermate controls (4.02 ms(2) +/- 1.17; n=6, G alpha(-/-)(i2)) mice have a selective attenuation of high-frequency (HF) power (0.73 ms(2) +/- 0.31; n=5, P<0.05). G alpha(-/-)(i1)/G alpha(-/-)(i3) and G alpha(-/-)(o) cohorts have nonsignificant changes in HF power. G alpha(o)-/- mice have a different basal HRV signature. The observed HRV phenotype in G alpha(i2)-/- mice was qualitatively similar to atropine (1 mg/kg)-treated controls [and mice treated with the GIRK channel blocker tertiapinQ (0.05 mg/kg)]. Maximal cardioinhibitory response to the M-2-receptor agonist carbachol (0.5 mg/kg) compared with basal heart rate was attenuated in G alpha(-/-)(i2) mice (0.08 +/- 0.04; n=6) compared to control (0.27 +/- 0.04; n=7 P<0.05). Our data suggest a selective defect of parasympathetic heart rate modulation in mice with G alpha(i2) deletion. Mice with G alpha(o) deletion also have a defect in short-term heart rate dynamics, but this is qualitatively different to the effects of atropine, tertiapinQ, and G alpha(i2) deletion. In contrast, G alpha(i1) and G alpha(i3) do not appear to be essential for parasympathetic responses in vivo.