Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Abstract

Two subtypes of ␤-adrenoceptors, ␤1 and ␤2, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human ␤2-adrenoceptors survive high-expression levels, unlike mice overexpressing ␤1-adrenoceptors. We examined the role of inhibitory Gi proteins, known to be activated by ␤2-but not ␤1-adrenoceptors, on the chronic effects of human ␤2-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where G␣i2, a functionally important cardiac Gi ␣-subunit, was inactivated by targeted gene deletion. Survival of ␤2-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of G␣i2. Homozygous knockout͞␤2-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout͞␤2-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with ␤2-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout͞␤2-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment in vitro fully restored channel activity and enhanced channel activity in cells from homozygous G␣i2 knockout animals. Cardiac G␣i3 protein was increased in all G␣i2 knockout mouse strains. Our results demonstrate that G␣i2 takes an essential protective part in chronic signaling of overexpressed ␤2-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by ␤2-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by G␣i3. This result indicates that subtype-specific signaling of ␤2-adrenoreceptor functionally bifurcates at the level of Gi, leading to different effects depending on the G␣ isoform.L-type calcium channel ͉ single channel recording ͉ mouse genetics ͉ survival curve ͉ pertussis toxin C ardiac stimulatory catecholamine effects are mediated by both ␤ 1 -and ␤ 2 -adrenergic receptors (␤-adrenoceptors), mainly through cAMP-dependent protein kinase A-catalyzed phosphorylation of cardiac proteins involved in calcium homeostasis, such as phospholamban and the L-type calcium channel. Evidently, this pathway is compromised in heart failure. Because of the clear-cut evidence that ␤ 2 -adrenoceptors mediate acute functional effects in human cardiomyocyte in vitro (1, 2) and in vivo (3), a rationale for ␤ 2 -adrenoreceptor gene therapy exists (4-6). Whether and where ␤ 2 -adrenoreceptor stimulation or inhibition, by pharmacological or genetic means, will have its place in heart failure therapy is an open question (7-9).Inherent in the clinical discussion is recent molecular insight into differences between cardiac ␤ 1 -and ␤ 2 -adrenoreceptor stimulation at the signal-transduction level (10, 11). In rat cardiomyocytes, a ␤ 2 -agonist, zinterol, was shown to increase calcium current in a manner qualitatively distinct from ␤ 1 -adrenoreceptor stimu...

Gαi2 Is the Essential Gαi Protein in Immune Complex–Induced Lung Disease

“…2), and this may also account for some of the enhanced responses observed in Ga i3 deficiency. Further studies will be needed to test the possibility of an antagonistic interplay between Ga i2 and Ga i3 in the transendothelial migration of neutrophils, as has been suggested previously for CXCR3-mediated signaling in T cells (41) and for the G i -specific regulation of calcium channels in cardiomyocytes (42,43).…”

EP4Prostanoid Receptor Coupling to a Pertussis Toxin-Sensitive Inhibitory G Protein

“…Thus, transgenic overexpression of ␤ 1 -adrenergic receptors in mice leads to cardiac hypertrophy, heart failure, and early death, whereas, overexpression of the ␤ 2 -adrenergic receptor actually improves cardiac function and does not adversely affect life span (Xiao et al, 1999b). Although cardiac ␤ 2 -adrenergic receptors can couple to G␣ s , it has been found that the protective effects of ␤ 2 -adrenergic receptor over expression depend upon coupling to G␣ i2 and G␣ i3 (Foerster et al, 2003). At present, the physiological and pathophysiological consequences of the unique signaling properties of the EP 4 receptor are unknown.…”

Crosstalk between Gi and Gq/Gs pathways in airway smooth muscle regulates bronchial contractility and relaxation

“…Taken together with the various animal models of asthma, an increase in G αi may be a generalized response to cellular hypertrophy, which in asthma contributes to the increased ASM mass (22). Although G αi2 is not increased in hearts overexpressing β 2 AR, coupling of β 2 AR to G i appears to provide protection against β 2 AR-mediated cardiomyopathy (23).…”