Ligand-Binding Sites on Calmodulin

Abstract

Calcium plays a pivotal role as an intracellular messenger in all eukaryotic cells. In resting cells the Ca²⁺ level is kept as low as 10^–7 M. A series of membrane-bound exchange proteins and ATP-driven pump proteins are responsible for excreting the Ca²⁺ into the extracellular environment or into intracellular organelles that function as calcium stores. Taken together, these proteins produce a 10 000-fold gradient of Ca²⁺ over the plasma membrane, thus creating a situation that lends itself to a regulatory function (Rasmussen 1983). A hormonal or nerval impulse can generate an influx of Ca²⁺ into the cytoplasm through the calcium channels. This influx gives rise to a transiently increased Ca²⁺ level inside the cell. Although the Ca²⁺ concentration in an activated cell may differ widely between various cell types, it is generally around 10^–6 M, which represents a tenfold increase from the resting level of 10^–7 M (Rasmussen 1983). This situation is schematically depicted in Fig. 1. As a second step, the transient increase in intracellular Ca²⁺ needs to be translated into metabolic or contractile responses. To this end, nature has deployed a unique class of calcium-binding proteins. Upon binding Ca²⁺ they undergo a large conformational change which allows them to interact with and activate specific target proteins. For example, in skeletal and cardiac muscles the protein troponin C is the calcium-binding component which triggers contraction. In smooth muscle tissues the homologous protein calmodulin (CaM) is responsible for the Ca²⁺ triggering of the initiation of contraction (see Chap. 3).