The complex cellular and physiological processes in living organisms require finely tuned regulation at the molecular level to ensure the adaptability of, for example, an animal or a plant to its habitat. To this end, numerous molecules exist that intervene in processes such as cell communication, metabolism or cell division. One of these molecules is the protein calmodulin, which, with the help of calcium, influences the function of many other biologically active proteins.
What is calmodulin?
Calmodulin is an intracellular regulatory protein that binds calcium ions. Based on its structure, it belongs to the group of EF-hand proteins. The shape of calmodulin, which consists of 148 amino acids and is 6.5 nm long, resembles a dumbbell. The molecular mass of this protein molecule is about 17 kDa. Due to its biological function in signal transduction within cells, calmodulin can also be classified as a second messenger, i.e. a secondary messenger that is not itself enzymatically active. In the two spherical domains of the protein, there are two helix-loop-helix motifs each at a distance of 1.1 nm, to which a total of four calcium ions can be bound. This structure is referred to as an EF-hand. The EF-hand structures are connected by hydrogen bonds between the antiparallel beta-sheets of calmodulin.
Function, action, and roles
Calmodulin requires three to four bound calcium ions per molecule to be active. When activated, the calcium-calmodulin complex formed is involved in the regulation of a variety of receptors, enzymes, and ion channels with a wide range of functions. Among the enzymes regulated are the phosphatase calcineurin, which plays an important role in the regulation of the immune response, and the endothelial nitric oxide synthase (eNOS), which produces NO, which, among other things, is responsible for the relaxation of smooth muscle and thus for the dilation of blood vessels. In addition, at low calcium concentrations adenylate cyclase (AC) is activated, whereas at high calcium concentrations its enzymatic counterpart, phosphodiesterase (PDE), is activated. Thus, a temporal sequence of regulatory mechanisms is achieved: initially, AC initiates a signaling pathway via the production of cyclic AMP (cAMP); later, this pathway is switched off again by its counterpart PDE via cAMP degradation. However, the regulatory effect of calmodulin on protein kinases such as CaM kinase II or myosin light chain kinase (MLCK) is particularly well known and will be discussed in some detail below. CAMKII can bind a phosphate residue to various proteins and thereby influence energy metabolism, permeability to ions and the release of neurotransmitters from cells. CAMKII is present in particularly high concentrations in the brain, where it is thought to play an important role in neuronal plasticity, i.e. all learning processes. But calmodulin is also indispensable for movement processes. In the resting state, the concentration of calcium ions in a muscle cell is very low and calmodulin is therefore inactive. However, when the muscle cell is excited, calcium flows into the cell plasma and occupies the four binding sites on calmodulin as a cofactor. This can now activate myosin light chain kinase, resulting in a shift in the contractile fibers in the cell, thus enabling muscle contraction. Other lesser-known enzymes under the influence of calmodulin include guanylate cyclase, Ca-Mg-ATPase, and phospholipase A2.
Formation, occurrence, properties, and optimal levels
Calmodulin is found in all eukaryotes, which include all plants, animals, fungi, and the group of amoeboid organisms. Because the calmodulin molecule in these organisms is usually relatively similar in structure, it can be assumed that it is a developmentally ancient protein that arose early in evolution. As a rule, calmodulin is present in relatively large quantities in the plasma of a cell. In the cytosol of nerve cells, for example, the usual concentration is about 30-50 μM, or 0.03-0.05 mol/L. The protein is formed in the context of transcription and translation by means of the CALM gene, of which there are three alleles known to date, designated CALM-1, CALM-2, and CALM-3.
Diseases and disorders
There are some chemical substances that can exert an inhibitory effect on calmodulin and are therefore known as calmodulin inhibitors.In most cases, their inhibitory effect is based on the fact that they transport calcium out of the cell and thus withdraw it from calmodulin, which is then only present in an inactive state. These inhibitory substances include, for example, W-7. In addition, some phenothiazine psychotropic drugs inhibit calmodulin. As broad as the regulatory functions of calmodulin are, as diverse are the conceivable defects and disorders when the protein can no longer be activated by the cofactor calcium and thus the regulated target enzymes are in turn less active. Deficient activation of CAMKII, for example, can result in a restriction of neuronal plasticity, which forms the basis for learning processes. Decreased activation of MLCK impairs muscle contraction, which can lead to movement disorders. Lower activation of the enzyme calcineurin due to calmodulin deficiency would affect the body’s immune response, and lower activation of eNOs would lead to lower NO concentrations. The latter causes problems especially where nitric oxide is otherwise supposed to prevent unwanted blood clotting and dilate vessels for the purpose of better blood flow. However, it should also be mentioned at this point that under certain conditions the calcium sensor frequenin can take over the biological functions of calmodulin and thus replace the molecule.
