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 alpha subunit of G(i2) protein (G(i2)alpha) or of the alpha subunit of G(o) protein (G(o)alpha). Preparations were stimulated with carbachol alone or after pretreatment with the beta-adrenoceptor agonist isoprenaline. For comparison, the effects of carbachol on L-type Ca(2+)-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 Ca(2+)-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 G(i2)alpha and G(o)alpha mediate the vagal stimulation in the atrium. Moreover, different G proteins mediate the effect of carbachol in ventricle compared with atrium.
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 alpha subunit of G(i2) protein (G(i2)alpha) or of the alpha subunit of G(o) protein (G(o)alpha). Preparations were stimulated with carbachol alone or after pretreatment with the beta-adrenoceptor agonist isoprenaline. For comparison, the effects of carbachol on L-type Ca(2+)-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 Ca(2+)-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 G(i2)alpha and G(o)alpha mediate the vagal stimulation in the atrium. Moreover, different G proteins mediate the effect of carbachol in ventricle compared with atrium.
Authors: M O Sowell; C Ye; D A Ricupero; S Hansen; S J Quinn; P M Vassilev; R M Mortensen Journal: Proc Natl Acad Sci U S A Date: 1997-07-22 Impact factor: 11.205
Authors: J Neumann; U Vahlensieck; P Boknik; B Linck; H Lüss; F U Müller; G P Matherne; W Schmitz Journal: Br J Pharmacol Date: 1999-12 Impact factor: 8.739
Authors: Gary L Aistrup; Ivan Cokic; Jason Ng; David Gordon; Hemanth Koduri; Suzanne Browne; Dorina Arapi; Yogita Segon; Jacob Goldstein; Abigail Angulo; J Andrew Wasserstrom; Jeffrey J Goldberger; Alan H Kadish; Rishi Arora Journal: Heart Rhythm Date: 2011-08-25 Impact factor: 6.343
Authors: Peter Boknik; Katharina Drzewiecki; John Eskandar; Ulrich Gergs; Stephanie Grote-Wessels; Larissa Fabritz; Paulus Kirchhof; Frank U Müller; Frank Stümpel; Wilhelm Schmitz; Norbert Zimmermann; Uwe Kirchhefer; Joachim Neumann Journal: Front Pharmacol Date: 2018-01-22 Impact factor: 5.810