Go but not Gi2 or Gi3 is required for muscarinic regulation of heart rate and heart rate variability in mice.
Muscarinic receptor-mediated cardiac parasympathetic activity is essential for regulating heart rate and heart rate variability (HRV). It has not been clear which G(i)/G(o) protein is responsible for these effects. We addressed this question using knockout mice that lack G protein alpha(i2), alpha(i3), or alpha(o) specifically. Unlike previously reported, our alpha(o)-null mice had significantly more survivors with normal life span. Isolated hearts from alpha(o)-null mice demonstrated much less sensitivity to the negative chronotropic effects of the muscarinic agonist carbachol to lower heart rate at baseline and a more profound effect under the stimulation of the beta-adrenergic agonist isoproterenol. In the presence of parasympathetic activation indirectly produced by methoxamine, an alpha(1)-adrenergic agonist, alpha(o)-null mice showed markedly decreased HRV compared with wild-type control mice. These differences in heart rate and HRV were not observed in alpha(i2)-null or alpha(i3)-null mice. Our findings establish an essential role for alpha(o) G protein in the anti-adrenergic effect of carbachol on heart rate regulation.
Duan
Sheng Zhong
SZ
Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Christe
Michael
M
Milstone
David S
DS
Mortensen
Richard M
RM
D000818:Animals; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D011976:Receptors, Muscarinic / Q000378:metabolism*
D011976:Receptors, Muscarinic; D019204:GTP-Binding Proteins; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C417708:Gnai3 protein, mouse