The multifunctional calcium/calmodulin-dependent protein kinase: from form to function.

Abstract

The regulation of cellular function by hormones and extracellular molecules, which bind to cell surface receptors, is initiated by signal transduction mech­ anisms at the plasma membrane that lead to the generation of intracellular signals, or second messengers. These second messengers interact with specific target molecules to initiate a cascade of biochemical events leading to a change in cellular function. A variety of intracellular second messengers, including divalent metals, phospholipid metabolites, and cyclic nucleotides, are known to be generated in response to extracellular stimuli. Calcium acts as an intra­ cellular second messenger in species as diverse as yeast to humans and is involved in cellular processes ranging from contraction to secretion to gene expression. Elevation of cytosolic calcium can occur by influx via regulated ion channels and transporters, or by release from intracellular stores via recep­ tor-generated second messengers (Figure 1). Cells contain a number of intra­ cellular calcium-binding proteins, and in most cell types, the major calcium­ binding protein is calmodulin (44, 91), an -17 kDa, heat-stable protein that binds four calcium ions with an overall high affinity of -1 11 M. This complex of 4(Ca)-calmodulin activates downstream targets. Although the importance of calcium as an intracellular messenger has been long recognized, identifica-