Phospholamban: A Critical Regulator of SERCA2a
PLN, a 52-amino acid SR transmembrane phosphoprotein, principally controls the activity of SERCA2a in cardiac myocytes. The structure and function of PLN are extensively reviewed elsewhere (Shaikh et al., 2016; Haghighi et al., 2014; Traaseth et al., 2008). SERCA2a and PLN interact at their cytoplasmic and transmembrane domains. PLN inhibits SERCA2a activity through direct interaction in its unphosphorylated form, whereas the phosphorylated form of PLN dissociates from SERCA2a. Phosphorylation of PLN relieves its inhibition on SERCA2a activity following phosphorylation at serine-16 and threonine-17 by PKA and CAMKII, respectively (Kranias and Hajjar, 2012; Frank et al., 2003). Under physiological conditions, phosphorylation at serine- 16 by PKA contributes to an increase in the rate of Ca2+ uptake into the SR. PLN is mostly responsible for the lucitropic effect on the heart by b-adrenergic stimulation, because PLN-deficient mice display maximal cardiac contractility and relaxation in the absence of any catecholamine stimulation (Luo et al., 1996).
In addition to phosphorylation, PLN activity is tightly regulated in a yin-yang mode: myocardial SR possesses phosphatase activity capable of dephosphorylating PLN by phosphatase type 1 and type 2A (Nicolaou and Kranias, 2009; Ikeda et al., 2008). The activity of phosphatase type 1 (PP-1) is decreased by phosphatase inhibitor-1 (I-1). I-1 can be activated through phosphorylation by PKA (Gupta et al., 1996; Huang et al., 1999; El-Armouche et al., 2003) or PKCa (Braz et al., 2004). Successful PP-1 isoform knockdown was achieved for each isoform without affecting the expression of the other isoforms. PP-1b knockdown most significantly enhanced the Ca2+ transient and cell shortening by augmenting PLN phosphorylation at baseline and with low-dose isoproterenol stimulation (10 nM). Interestingly, PP-1b was preferentially associated with SERCA and PLN in GFP-PP-1-transfected cardiomyocytes, as well as in canine longitudinal SR preparations (Aoyama et al., 2011).
