期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 106, 期 38, 页码 16269-16274出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0901679106
关键词
cAMP; cardiac contractility; G proteins; NDPK; zebrafish
资金
- Deutsche Forschungsgemeinschaft [Wi1373/9-1, Wi1373/9-2, Ro2173/2-2, Ro2173/3-1]
- Bundesministerium fur Bildung und Foschung [01GS0108, 01GS0420, 01GS0836]
- National Institute of Health/National Cancer Institute [CA76496]
Heterotrimeric G proteins in physiological and pathological processes have been extensively studied so far. However, little is known about mechanisms regulating the cellular content and compartmentalization of G proteins. Here, we show that the association of nucleoside diphosphate kinase B ( NDPK B) with the G protein beta gamma dimer (G beta gamma) is required for G protein function in vivo. In zebrafish embryos, morpholino-mediated knockdown of zebrafish NDPK B, but not NDPK A, results in a severe decrease in cardiac contractility. The depletion of NDPK B is associated with a drastic reduction in G beta(1 gamma 2) dimer expression. Moreover, the protein levels of the adenylyl cyclase (AC)-regulating G alpha s and G alpha(i) subunits as well as the caveolae scaffold proteins caveolin-1 and -3 are strongly reduced. In addition, the knockdown of the zebrafish G beta(1) orthologs, G beta(1) and G beta(1) like, causes a cardiac phenotype very similar to that of NDPK B morphants. The loss of G beta(1)/G beta(1like) is associated with a down-regulation in caveolins, AC-regulating G alpha-subunits, and most important, NDPK B. A comparison of embryonic fibroblasts from wild-type and NDPK A/B knockout mice demonstrate a similar reduction of G protein, caveolin-1 and basal cAMP content in mammalian cells that can be rescued by re-expression of human NDPK B. Thus, our results suggest a role for the interaction of NDPK B with G beta gamma dimers and caveolins in regulating membranous G protein content and maintaining normal G protein function in vivo.
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