Nitric oxide (NO) is a ubiquitous signaling molecule that regulates various cellular physiological and pathological events in virtually all vital organs. The synthesis of NO is catalyzed primarily by three isoforms of NO synthase (NOS), which were originally named after the tissues in which these enzymes were first characterized and cloned (ie nNOS-neuronal, iNOS-inducible or inflammation-related, and eNOS-endothelial)[1]. Accumulating evidence suggests that all of the three NOS isozymes are expressed and distributed in various cell types in the cardiovascular system far beyond their initial identified cell types and locations. Besides the extensive studies on transcriptional control of NOS expression and the Ca2+-dependent activation of eNOS and nNOS, there has been an increasing recognition that post-translational modification of NOS may effectively modulate the enzyme activity which in turn tightly controls the cellular viability and function through NO production at the right time, right location, and right amount [2]. Among these posttranslational regulation mechanisms of eNOS, the kinase-mediated protein phosphorylation plays a critical role [3, 4]. Several studies were simultaneously published in 1999, which provided direct evidence that eNOS activity may be substantially modulated through phosphorylation by Akt/PKB (Protein kinase B)[5-8] or AMPK (AMP-activated protein kinase)[9]. More recently, there have been a number of studies on the regulatory role of eNOS phosphorylation in determining the enzyme activity, independently or interplaying with the sub-cellular localization of eNOS [10, 11].

In the current issue of Journal of Molecular and Cellular Cardiology, Mount and colleagues have provided a timely update on multi-site eNOS phosphorylation, its active role in regulating NO synthesis under various cardiovascular physiological and pathological processes [12]. The authors reviewed the current knowledge on eNOS phosphorylation including a complex picture of the phosphorylation site-specific effects on eNOS enzyme activity. The discussion was particularly focused on each of the known eNOS phosphorylation sites (namely serine 114, 615, 633, 1177 and threonine 495) and their regulation by a number of kinases (including Akt/PKB, AMPK, PKA, PKC, PKG, and CaMK-2) in response to a variety of pathophysiological or pharmacological stimuli [12]. In addition, the authors discussed about the biological significance of eNOS phosphorylation in cardiovascular system and there is no need to repeat all the details in this editorial commentary. Nevertheless, as the authors pointed out, the current understanding of multi-