Phosphatase-1 inhibitor-1 is down-regulated in heart failure but hyperactive in atrial fibrillation, highlighting controversial issues on whether it should be therapeutically reinforced or inhibited.
This review highlights the complex and controversial role of Phosphatase-1 inhibitor-1 in heart failure and arrhythmias, suggesting future directions for its therapeutic potential.
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.
Wittköpper et al. (Thu,) conducted a review in Heart failure and arrhythmias. Phosphatase-1 inhibitor-1 (I-1) was evaluated. Phosphatase-1 inhibitor-1 is down-regulated in heart failure but hyperactive in atrial fibrillation, highlighting controversial issues on whether it should be therapeutically reinforced or inhibited.