Intracellular calpain activity: a pointer to disorders of the ageing brain?

[xchrom]

http://www.elpais.com/articulo/sociedad/Intracellular/calpain/activity/pointer/to/disorders/of/the/ageing/brain/elpepusoc/20111128elpepusoc_14/Tes



Calpain enzymes are precision instruments; they are like a surgeon's scalpel whereas enzymes found in the stomach are like a hammer. Calpain enzymes that are inside the cells cleave, or split, several proteins at a specific point or site: other enzymes merely break up proteins into smaller units, namely peptides. (Peptides, in turn, are made up of amino acids.)

If a protein breaks up, it can no longer carry out its specific function. Calpains, therefore, influence the biological function of the substrates?proteins, in this case. The exact effect of this cleavage depends a great deal on the role assigned to the intact protein in a normal cell but it is known that the splitting is associated with the development of such diseases as Alzheimer's, Huntington's, and Parkinson's as well as non-insulin-dependent diabetes. Although calpains are apparently involved in many physiological and pathological changes, their functions are far from clear as yet.

Different methods are used to study the processes in which calpains are involved. One method stimulates excess production of calpains by manipulating the appropriate gene or genes controlling the expression of the calpains whereas another removes them altogether: we can then observe what happens when there is excess of calpain or when it is missing altogether. Calpain function can also be inhibited by small molecules - the inhibitors - which can enter a cell through its membrane, and we can compare the cells so treated with normal, untreated cells to study the role of the calpain that was thus inhibited. Unfortunately, this method is not precise because the known inhibitors are not selective enough?they inhibit other enzymes too, which means that we cannot say with confidence that the change we observed was only due to the particular calpain. Manipulation of specific genes is a precise method but the technique needs a well-equipped laboratory and is not simple.

Compounds that are highly active biologically and are selective in their effects often cannot cross the cell membrane and thus cannot act on their target within the cells. The solution is therefore to attach such compounds to peptides - cell-penetrating peptides - that can cross the cell membrane to enter a cell with their cargo.

[HuckleB]

1. Also recommended.