Stamler, J. S. | bioRxiv Science

bioRxiv2026

S-nitrosylation of protein kinase A is required for its activation by GPCRs

Stimulation of many G protein-coupled receptors (GPCRs) increases cyclic adenosine monophosphate (cAMP) and nitric oxide (NO). While cAMP-dependent activation of protein kinase A (PKA) is a central regulatory mechanism, a parallel role for NO in GPCR transduction has not been established. Here we show that upon stimulation of multiple GPCRs in heart, brain, and fat, the regulatory subunits of PKA undergo enzymatic S-nitrosylation by SNO-CoA-assisted nitrosylase (SCAN). S-nitrosylation by SCAN is required for dissociation of PKA holoenzymes and activation of PKA. In transgenic and cardiovascular disease models, impaired adrenergic stimulation is identified with deficient S-nitrosylation of PKA, which can be rescued by the drug sodium nitroprusside. Our work suggests a new understanding of GPCR physiology with direct application to the clinical setting.

physiology↗

bioRxiv2025

The denitrosylase SCoR2 controls cardioprotective metabolic reprogramming

Acute myocardial infarction (MI) is a leading cause of morbidity and mortality, and therapeutic options remain limited. Endogenously generated nitric oxide (NO) is highly cardioprotective, but protection is not replicated by nitroso-vasodilators (e.g., nitrates, nitroprusside) used in clinical practice, highlighting specificity in NO-based signaling and untapped therapeutic potential. Signaling by NO is mediated largely by S-nitrosylation, entailing specific enzymes that form and degrade S-nitrosothiols in proteins (SNO-proteins), termed nitrosylases and denitrosylases, respectively. SNO-CoA Reductase 2 (SCoR2; product of the Akr1a1 gene) is a recently discovered protein denitrosylase. Genetic variants in SCoR2 have been associated with cardiovascular disease, but its function is unknown. Here we show that mice lacking SCoR2/Akr1a1 exhibit robust protection in an animal model of MI. SCoR2 regulates ketolytic energy availability, antioxidant levels and polyol homeostasis via S-nitrosylation of key metabolic effectors. Human cardiomyopathy shows reduced SCoR2 expression and an S-nitrosylation signature of metabolic reprogramming, mirroring SCoR2-/- mice. Deletion of SCoR2 thus coordinately reprograms multiple metabolic pathways--ketone body utilization, glycolysis, pentose phosphate shunt and polyol metabolism--to limit infarct size, establishing SCoR2 as a novel regulator in the injured myocardium and a potential drug target. Impact statementMice lacking the denitrosylase enzyme SCoR2 demonstrate robust cardioprotection resulting from coordinate reprogramming of multiple metabolic pathways. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/642752v2_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@72bfbborg.highwire.dtl.DTLVardef@189cbc4org.highwire.dtl.DTLVardef@1a0cc51org.highwire.dtl.DTLVardef@1c61004_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗