Control of protein phosphorylation/dephosphorylation events occurs through regulation of protein kinases and phosphatases. The phosphatase type 1 (PP-1) compromises the main activity of Ser/Thr protein phosphatases in the heart. Inhibitor-1 (I-1) was the first endogenous molecule found to specifically inhibit PP-1. 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 -adrenoceptor ( -AR) signaling. I-1 was found to be downregulated and hypophosphorylated 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 been recently 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 -AR signaling.
Control of protein phosphorylation/dephosphorylation events occurs through regulation of protein kinases and phosphatases. The phosphatase type 1 (PP-1) compromises the main activity of Ser/Thr protein phosphatases in the heart. Inhibitor-1 (I-1) was the first endogenous molecule found to specifically inhibit PP-1. 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 -adrenoceptor ( -AR) signaling. I-1 was found to be downregulated and hypophosphorylated 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 been recently 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 -AR signaling.