Transnitrosylating nitric oxide species directly activate type I protein kinase A, providing a novel adenylate cyclase-independent cross-talk to beta-adrenergic-like signaling.
The transnitrosylating nitric oxide (NO) donor nitrocysteine (CysNO) induced a disulfide bond between the two regulatory RI subunits of protein kinase A (PKA). The conventional NO donor S-nitroso-N-acetylpenicillamine failed to do this, consistent with our observation that it also did not promote protein S-nitrosylation. This disulfide oxidation event activated PKA and induced vasorelaxation independently of the classical beta-adrenergic or NO signaling pathway. Activation of PKA had also been anticipated to exert a positive inotropic effect on the myocardium but did not. The lack of positive inotropy was explained by CysNO concomitantly activating protein kinase G (PKG) Ialpha. PKG was found to exert a partial negative inotropic influence regardless of whether PKA was activated by classical beta-receptor stimulation or by disulfide bond formation. This work demonstrates that NO molecules that can induce S-nitrosylation directly activate type I PKA, providing a novel cross-talk to beta-adrenergic-like signaling without receptor or adenylate cyclase stimulation. However, the expected positive inotropic consequences of PKA activation by this novel mechanism are countermanded by the simultaneous dual activation of PKGIalpha, which is also activated by CysNO.
Burgoyne
Joseph R
JR
Cardiovascular Division, The Rayne Institute, St. Thomas' Hospital, King's College London, London SE17EH, United Kingdom.
Eaton
Philip
P
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D003545:Cysteine / Q000378:metabolism; D004220:Disulfides / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000378:metabolism* / Q000494:pharmacology; D009574:Nitro Compounds / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D004220:Disulfides; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D017868:Cyclic AMP-Dependent Protein Kinases; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D017869:Cyclic GMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D003545:Cysteine