Novel function of the regulatory subunit of protein kinase A: regulation of cytochrome c oxidase activity and cytochrome c release.
There have been speculations that the regulatory (R) subunit of the cAMP-dependent protein kinase (PKA) may have other functions. A recent study has shown that the catalytic (C) subunit of PKA may be regulated in a cAMP- and R subunit-independent manner. However, evidence linking a function to the R subunit apart from inhibiting the C subunit has been elusive. In this report, interaction cloning experiments showed that the RIalpha subunit association with the cytochrome c oxidase subunit Vb (CoxVb) is cAMP-sensitive. Interaction was detected with a GST-RIalpha fusion protein as well as by coimmunoprecipitation. Transient treatment with cAMP-elevating agents inhibited cytochrome c oxidase in Chinese hamster ovary (CHO) cells with a concomitant decrease in cytochrome c levels in the mitochondria and an increase in its release into the cytosol. Furthermore, mutant cells harboring a defective RIalpha show increased cytochrome c oxidase activity and also constitutively lower levels of cytochrome c in comparison to either the wild-type cells or the C subunit mutant. These results suggest a novel mechanism of cAMP signaling through the interaction of RIalpha with CoxVb thereby regulating cytochrome c oxidase activity as well as the cytochrome c levels.
Department of Medicine and Pharmacology, Robert Wood Johnson Medical School, New Brunswick, New Jersey 08901, USA.
W L
WL
Yang
L
L
Iacono
W M
WM
Tang
K V
KV
Chin
D000818:Animals; D016466:CHO Cells; D003001:Cloning, Molecular; D006224:Cricetinae; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D003574:Cytochrome c Group / Q000378:metabolism*; D003576:Electron Transport Complex IV / Q000378:metabolism*; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D011233:Precipitin Tests; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013347:Subcellular Fractions / Q000201:enzymology
D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D003574:Cytochrome c Group; C517835:Prkar1a protein, mouse; D011993:Recombinant Fusion Proteins; D003576:Electron Transport Complex IV; D005982:Glutathione Transferase; D017868:Cyclic AMP-Dependent Protein Kinases