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RECEPTORS AND SIGNALING PATHWAYS

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

¹British Heart Foundation, Laboratories and Department of Medicine, University College London, London, United Kingdom; and ²National Institute of Health Sciences, Research Triangle Park, North Carolina

Submitted 23 July 2008 ; accepted in final form 30 September 2008

Multiple isoforms of inhibitory G-subunits (G_i1,2,3, as well as G_o) are present within the heart, and their role in modulating pacemaker function remains unresolved. Do inhibitory G-subunits selectively modulate parasympathetic heart rate responses? Published findings using a variety of experimental approaches have implicated roles for G_i2, G_i3, and G_o in parasympathetic signal transduction. We have compared in vivo different groups of mice with global genetic deletion of Gi₁/G_i3, G_i2, and G_o against littermate controls using implanted ECG telemetry. Significant resting tachycardia was observed in G_i2^–/– and G_o^–/– mice compared with control and G_i1^–/–/G_i3^–/– mice (P < 0.05). Loss of diurnal heart rate variation was seen exclusively in G_o^–/– mice. Using heart rate variability (HRV) analysis, compared with littermate controls (4.02 ms² ± 1.17; n = 6, G_i2^–/–) mice have a selective attenuation of high-frequency (HF) power (0.73 ms² ± 0.31; n = 5, P < 0.05). G_i1^–/–/G_i3^–/– and G_o^–/– cohorts have nonsignificant changes in HF power. G_o^–/– mice have a different basal HRV signature. The observed HRV phenotype in G_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 M₂-receptor agonist carbachol (0.5 mg/kg) compared with basal heart rate was attenuated in G_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_i2 deletion. Mice with G_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_i2 deletion. In contrast, G_i1 and G_i3 do not appear to be essential for parasympathetic responses in vivo.

inhibitory G proteins; heart rate; heart rate variability; parasympathetic