Functional selectivity

Functional selectivity refers to the phenomenon in pharmacology that biologically active substances ( drugs, ligands ) to their binding to a receptor preferentially activate one of several possible signal transduction pathways. This phenomenon can be observed in principle at all receptors that are coupled to at least two different signal transduction pathways. Functional selectivity could be observed for several ligands to nuclear hormone receptors and G- protein-coupled receptors.

The observation of functional selectivity of a ligand can causally to the diversity of the studied effects (such as fast or slow-onset effects), different degrees of expression and activity of the receptor protein or properties of the ligands themselves are recycled. In the latter case one speaks of biased agonism, agonist- selective trafficking of ligand- selective agonism or stimulus.

Receptor oligomers

One reason for the appearance of the functional selectivity lies in the diversity of the aggregation forms of receptors. Physical interactions of receptor proteins with other proteins can cause conformational changes of the tertiary form of the receptor. This change in the overall shape of a receptor, in turn, may affect the affinity of G - proteins and the rest of the signal transduction. An example of this receptor protein - receptor interactions are oligomers. Examples of the selective response of signaling pathways depending on the response of different receptor aggregates are known. Thus, stimulation of the 5- HT2A protomer in the 5 -HT2A - mGlu2 receptor complex psychedelic effects that do not occur at the sole stimulation of the monomeric 5 -HT2A receptor; different G- proteins are involved in accordance. This functional selectivity is also the reason, but why the endogenous transmitter serotonin vasoconstriction and platelet aggregation triggers will not affect psychedelic. Lisuride, which behaves as an agonist at the 5- HT2AR monomer antagonized competitively effects of LSD and should therefore be regarded as protomer antagonist of the 5- HT2A mGluR heteromer. In addition, agents may affect the aggregation state of receptors. The ligand-induced change in the tertiary structure of the receptor can have an effect on the receptor -receptor affinity and can promote association or dissociation of receptors or protomers. The antidepressants desipramine and citalopram carrying heteromerization of sst5 and dopamine D2 receptors, the underlying mechanism remains unknown, since these agents are not classical binding partners of these receptors. In the example change with altered level of aggregation, the signal paths.