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Multiple isoforms of inhibitory Gα-subunits (Gαi1,2,3, as well as Gα0) are present within the heart, and their role in modulating pacemaker function remains unresolved. Do inhibitory Gα-subunits selectively modulate parasympathetic heart rate responses? Published findings using a variety of experimental approaches have implicated roles for Gαi2, Gαi3, and Gα0 in parasympathetic signal transduction. We have compared in vivo different groups of mice with global genetic deletion of Giα1/Gαi3, Gαi2, and Gα0 against littermate controls using implanted ECG telemetry. Significant resting tachycardia was observed in Gαi2-/- and Gα0-/- mice compared with control and Gαi1-/- /Gαi3-/- mice (P < 0.05). Loss of diurnal heart rate variation was seen exclusively in Gα0-/- mice. Using heart rate variability (HRV) analysis, compared with littermate controls (4.02 ms² ± 1.17; n = 6, Gαi2-/-) mice have a selective attenuation of high-frequency (HF) power (0.73 ms² ± 0.31; n = 5, P < 0.05). Gαi1-/- /Gαi3-/- and Gα0-/- cohorts have nonsignificant changes in HF power. Gα0-/- mice have a different basal HRV signature. The observed HRV phenotype in Gαi2-/- 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 M2-receptor agonist carbachol (0.5 mg/kg) compared with basal heart rate was attenuated in Gαi2-/- 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 Gαi2 deletion. Mice with Gα0 deletion also have a defect in short-term heart rate dynamics, but this is qualitatively different to the effects of atropine, tertiapinQ, and Gαi2 deletion. In contrast, Gαi1 and Gαi3 do not appear to be essential for parasympathetic responses in vivo. [ABSTRACT FROM AUTHOR]

Reciprocal physiological modulation of heart rate is controlled by the sympathetic and parasympathetic systems acting on the sinoatrial (SA) node. However, there is little direct in vivo work examining the role of stimulatory and inhibitory G protein signaling in the SA node. Thus, we designed a study to examine the role of the stimulatory (Gs) and inhibitory G protein (Gi2) in in vivo heart rate regulation in the SA node in the mouse. We studied mice with conditional deletion of Gαs and Gαi2 in the conduction system using cre-loxP technology. We crossed mice in which cre recombinase expression was driven by a tamoxifeninducible conduction system-specific construct with "Gαs floxed" and "Gαi2 floxed" mice. We studied the heart rate responses of adult mice compared with littermate controls by using radiotelemetry before and after administration of tamoxifen. The mice with conditional deletion of Gαs and Gαi2 had a loss of diurnal variation and were bradycardic or tachycardic, respectively, in the daytime. In mice with conditional deletion of Gαs, there was a selective loss of low-frequency power, while with deletion of Gαi2, there was a loss of high-frequency power in power spectral analysis of heart rate variability. There was no evidence of pathological arrhythmia. Pharmacological modulation of heart rate by isoprenaline was impaired in the Gαs mice, but a muscarinic agonist was still able to slow the heart rate in Gαi2 mice. We conclude that Gαs- and Gαi2-mediated signaling in the sinoatrial node is important in the reciprocal regulation of heart rate through the autonomic nervous system. [ABSTRACT FROM AUTHOR]