title: Phosphatase-1 inhibitor-1 in physiological and pathological β-adrenoceptor signalling.
abstract: Control of protein phosphorylation-dephosphorylation events occurs through regulation of protein kinases and phosphatases. Phosphatase type 1 (PP-1) provides the main activity of serine/threonine protein phosphatases in the heart. Inhibitor-1 (I-1) was the first endogenous molecule found to inhibit PP-1 specifically. Notably, I-1 is activated by cAMP-dependent protein kinase A (PKA), and the subsequent prevention of target dephosphorylation by PP-1 provides distal amplification of β-adrenoceptor (β-AR) signalling. I-1 was found to be down-regulated and hypo-phosphorylated in human and experimental heart failure but hyperactive in human atrial fibrillation, implicating I-1 in the pathogenesis of heart failure and arrhythmias. Consequently, the therapeutic potential of I-1 in heart failure and arrhythmias has recently been addressed by the generation and analysis of several I-1 genetic mouse models. This review summarizes and discusses these data, highlights partially controversial issues on whether I-1 should be therapeutically reinforced or inhibited and suggests future directions to better understand the functional role of I-1 in physiological and pathological β-AR signalling.
authors.affiliation: Department of Pharmacology, University Medical Center Göttingen, Georg August University Göttingen, Göttingen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Wittköpper
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: Ali
authors.initials: A
authors.lastname: El-Armouche
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000201:enzymology / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006331:Heart Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006333:Heart Failure / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D011506:Proteins; D011943:Receptors, Adrenergic, beta; C073882:phosphoprotein phosphatase inhibitor 1; D017868:Cyclic AMP-Dependent Protein Kinases; D054645:Protein Phosphatase 1