Agonists and Antagonists of Membrane-Bound Receptors

Abstract

Messenger molecules assume the task of conveying and transmitting information between cells. These molecules can be as small as single ions, but can also attain the formidable size of signaling peptides all the way to proteins. They bind to a membrane-bound receptor on the extracellular side to transmit signals. There are hardly any alternative pathways for these messenger molecules because substances such as dopamine, histamine, or adrenaline, and also peptides and proteins such as insulin, interleukins, angiotensin, endothelin, or neurokinin cannot cross the cell membrane. Ligand-binding signals are transmitted to the interior of the cell by a transition of the conformational state of the receptors. In the case of activation, the bound ligand stabilizes the active receptor conformation. For inhibition, the ligand binds to the receptor from the outside, which does not change the conformational equilibrium, but stabilizes the inactive conformation. Signal transmission does not occur. Both approaches can be beneficial for drug therapy. On the one hand, agonists are spoken of, and on the other, antagonists or inverse agonists are meant. G protein–coupled receptors (GPCR), which transect the membrane with seven helices, encompass a huge group of membrane-bound receptors. Agonists stimulate an activation of the coupled G protein in GPCRs, which initiates subsequent processes in the cell. The second class is made up by receptors that also penetrate the cell membrane with a helical segment. Dimerization is a prerequisite for their activation. The attached cytosolic tyrosine kinase domains in the interior of the cell begin to mutually phosphorylate one another. This transforms them into a state in which the functions of other proteins are turned on by phosphorylation. Another group of oligomeric membrane-bound receptors binds interleukins as messenger molecules. They also initiate kinase-dependent intracellular signaling pathways as a result of ligand binding. About a third of our pharmaceuticals act on GPCRs in a regulatory fashion. The picture is much less clear for the second class of membrane-bound receptors. These receptors are all regulated by large ligands making the development of a competitive, small xenobiotic extremely difficult (Sect. 10.6).