期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2003
卷号：100
期号：24
页码：14475-14480
DOI：10.1073/pnas.1936026100
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Two subtypes of {beta}-adrenoceptors, {beta}1 and {beta}2, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human {beta}2-adrenoceptors survive high-expression levels, unlike mice overexpressing {beta}1-adrenoceptors. We examined the role of inhibitory Gi proteins, known to be activated by {beta}2- but not {beta}1-adrenoceptors, on the chronic effects of human {beta}2-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where Gi2, a functionally important cardiac Gi -subunit, was inactivated by targeted gene deletion. Survival of {beta}2-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of Gi2. Homozygous knockout/{beta}2-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout/{beta}2-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with {beta}2-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout/{beta}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 Gi2 knockout animals. Cardiac Gi3 protein was increased in all Gi2 knockout mouse strains. Our results demonstrate that Gi2 takes an essential protective part in chronic signaling of overexpressed {beta}2-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by {beta}2-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by Gi3. This result indicates that subtype-specific signaling of {beta}2-adrenoreceptor functionally bifurcates at the level of Gi, leading to different effects depending on the G isoform.
