Death by protein kinase C inhibitor: a stressful event

The protein kinase C (PKC) family of Ser-/Thr-kinases is composed of three subfamilies: "classical" cPKCs, (alpha, betaI, beta II and gamma) which req uire both Ca2+ and diacylglycerol (DAG) for full activation; "novel" nPKCs (delta, epsilon, eta and 0) which require DAG but are Ca2+-independent: and "atypical" aPKCs (zeta and lambda /l) which require neither DAG nor Ca2+ ( reviewed in reference 1). All subfamilies are represented in the heart. wit h the alpha, delta,epsilon, zeta and lambda /t isoforms being most readily detected (reviewed in reference 2). Although PKC was first identified in 19 77 as a phospholipid- and Ca2+-dependent kinase, with the individual isofor ms being identified through to the mid-1990s, the physiological substrates of these kinases and the downstream effects of individual PKC isoforms stil l prove elusive. The generation of selective PKC inhibitors was expected to assist in identifying substrates and establishing the role(s) of these kin ases in biological responses, but high specificity among inhibitors is rare .(3) Nevertheless, the "selective" PKC inhibitors which are available have implicated PKC in a range of responses in the heart including cardiac myocy te hypertrophy (reviewed in reference 4) and, most notably, ischemic precon ditioning, a phenomenon in which a short period of ischemia protects the he art from a more prolonged ischemic episode (reviewed in reference 5).