Genetic disruption of G proteins, Gi2α or Goα, does not abolish inotropic and chronotropic effects of stimulating muscarinic cholinoceptors in atrium

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Abstract
Background and purpose: Classically, stimulation of muscarinic cholinoceptors exerts negative inotropic and chronotropic effects in the atrium of mammalian hearts. These effects are crucial to the vagal regulation of the heart beat. This effect is assumed to be mediated via GTP binding (G) proteins, because they can be abolished by Pertussis toxin. However, it is unknown which G proteins are involved. Experimental approach: We studied contractility in isolated left or right atrium from genetically manipulated mice with deletion of one of two G proteins, either of the α subunit of Gi2 protein (Gi2α) or of the α subunit of Go protein (Goα). Preparations were stimulated with carbachol alone or after pretreatment with the β‐adrenoceptor agonist isoprenaline. For comparison, the effects of carbachol on L‐type Ca2+‐channels in isolated ventricular cardiomyocytes were studied. Key results: The negative inotropic and chronotropic effects of carbachol alone or in the presence of isoprenaline were identical in atria from knockout or wild‐type mice. However, the effect of carbachol on isoprenaline‐activated L‐type Ca2+‐channel in isolated ventricular cardiomyocytes was greatly attenuated in both types of knockout mice studied. Conclusions and implications: These data imply that there is either redundancy of G proteins for signal transduction or that Pertussis toxin‐sensitive proteins other than Gi2α and Goα mediate the vagal stimulation in the atrium. Moreover, different G proteins mediate the effect of carbachol in ventricle compared with atrium.

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