Year: 2026
Type: preprint
Abstract: 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.
Institutions: University of California, Los Angeles, University of California, Davis, VA Northern California Health Care System, University of California San Diego, University Hospitals of Cleveland, University Hospitals Cleveland Medical Center, Case Western Reserve University, VA Greater Los Angeles Healthcare System
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: American Heart Association, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: PANX1 in Diabetic Cardiomyopathy: Molecular Mechanisms, Dysregulation of Cav1.2 by beta amyloid peptide, Sex-dependent regulation of cardiac cAMP, ECC, and arrhythmia by phosphodiesterases, A Molecular Approach to the Pathogenesis of Portal Hypertension, Postsynaptic Signaling by Norepinephrine and cAMP, Regulation of a cardiac b1AR/SERCA2 complex in heart failure, Novel Regulation of Renal Function by S-Nitrosylation, Lessons Learned from PKA: Assembly of Dynamic Macromolecular Switches
OpenAlex ID: W7162940892