In:
Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 98, No. 5 ( 2006-03-17), p. 659-666
Kurzfassung:
Cardiac automaticity is controlled by G protein–coupled receptors, such as adrenergic, muscarinic, and adenosine receptors. The strength and duration of G protein signaling is attenuated by regulator of G protein signaling (RGS) proteins acting as GTPase-activating proteins for Gα subunits; however, little is known about the role of endogenous RGS proteins in cardiac function. We created point mutations in Gα subunits that disrupt Gα-RGS binding and introduced them into embryonic stem (ES) cells by homologous recombination. Spontaneously contacting cardiocytes derived from the ES cells were used to evaluate the role of endogenous RGS proteins in chronotropic regulation. The RGS-insensitive Gα o G184S homozygous knock-in (Gα o GS/GS) cells demonstrated enhanced adenosine A 1 and muscarinic M 2 receptor–mediated bradycardic responses. In contrast, Gα i2 GS/GS cells showed enhanced responses to M 2 but not A 1 receptors. Similarly M 2 but not A 1 bradycardic responses were dramatically enhanced in Gα i2 GS/GS mice. Blocking G protein–coupled inward rectifying K + (GIRK) channels largely abolished the mutation-induced enhancement of the M 2 receptor–mediated response but had a minimal effect on A 1 responses. The Gα s -dependent stimulation of beating rate by the β 2 adrenergic receptor agonist procaterol was significantly attenuated in Gα o GS/GS and nearly abolished in Gα i2 GS/GS cells because of enhanced signaling via a pertussis toxin sensitive mechanism. Thus, endogenous RGS proteins potently reduce the actions of Gα i/o -linked receptors on cardiac automaticity. Furthermore, M 2 and A 1 receptors differentially use Gα i2 and Gα o and associated downstream effectors. Thus, alterations in RGS function may play a role in pathophysiological processes and RGS proteins could represent novel cardiovascular therapeutic targets.
Materialart:
Online-Ressource
ISSN:
0009-7330
,
1524-4571
DOI:
10.1161/01.RES.0000207497.50477.60
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2006
ZDB Id:
1467838-X
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