Diacylglycerol production, Ca²⁺ influx, and protein kinase C activation in sustained cellular responses

The focus of this review is on the role of protein kinase C (PKC) in the regulation of the secretion of aldosterone from the adrenal glomerulosa cell and of insulin from the β-cell of the Islets of Langerhans. These processes will be considered in the context of a model of how PKC functions as one component of a three-component, Ca²⁺-influx-diacylglycerol (DAG)-PKC, plasma membrane transducer involved in regulation of the sustained phase of these secretory responses. Within this context, the possible role of this transducer in the phenomenon of time-dependent potentiation (TDP) and time-dependent suppression (TDS) of these responses will also be considered. The initial physiological system in which the activation of PKC was reported to play a signaling role was that of platelet activation. In their initial studies, Takai et al. (1) showed that activation of both the calcium-calmodulin-dependent myosin light chain kinase, and PKC, a phospholipid- and calcium ion-dependent enzyme, were necessary for the full platelet response. They proposed that the activation of these two kinases were coincident events. This proposal was in keeping with the then current concept that when an extracellular messenger interacts with its receptor, intracellular messengers are produced that act concurrently to produce a cellular response. They proposed that the activation of these two kinases were coincident events. This proposal was in keeping with the then current concept that when an extracellular messenger interacts with its receptor, intracellular messengers are produced that act concurrently to produce a cellular response. In this view, hormone-receptor interaction is somewhat analogous to turning on and off a light switch, i.e. an intracellular signal of constant strength is produced as long as the switch is turned on, and once it is turned off, this system rapidly relaxes back to its original state. However, from more recent studies of cell activation, it has become clear that in many instances there is a temporal progression of signaling events when a cell is activated by an extracellular messenger. Thus, rather than operating more or less as a light switch, the activated receptor operates in a fashion analogous to the activation of a programmed tape of instructions. In this way, cells tell time, i.e. cell signaling is an historical process (2). In addition, our models of how signaling pathways regulate cellular responses have gone from the simple to the complex.