Functional selectivity

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In pharmacology, functional selectivity refers to the phenomenon that biologically active substances ( active ingredients , ligands ) can preferably activate one of several possible signal transduction pathways after they have bound to a receptor . In principle, this phenomenon can be observed on all receptors that are coupled to at least two different signal transduction pathways. Functional selectivity could be observed for different ligands on nuclear hormone receptors and G-protein-coupled receptors .

The observation of a functional selectivity of a ligand can causally be traced back to the differences in the investigated effects (e.g. effects that set in quickly or slowly), different levels of expression and activity of the receptor protein, or to properties of the ligand itself. In the latter case, one speaks of biased agonism , agonist-selective trafficking of stimulus or ligand-selective agonism .

Receptor oligomers

One reason for the appearance of functional selectivity is the diversity of the forms of aggregation of receptors. Physical interactions of receptor proteins with other proteins can cause conformational changes in the tertiary shape of the receptor. This change in the overall shape of a receptor can in turn affect the affinity for G proteins and the rest of the signal transduction. An example of these receptor-protein interactions are receptor oligomers . Examples of the selective response of signal pathways as a function of the response of different receptor aggregates are known. The stimulation of the 5-HT2A protomer in the 5-HT2A - mGlu2 receptor complex leads to psychedelic effects that do not occur when the monomeric 5-HT2A receptor is stimulated alone; accordingly, different G proteins are involved. This functional selectivity is also the reason why the endogenous transmitter serotonin triggers vasoconstriction and platelet aggregation but does not have a psychedelic effect. Lisuride , which acts as an agonist on the 5-HT2AR monomer, competitively antagonizes the effects of LSD and should therefore be regarded as a protomer antagonist of the 5-HT2A-mGluR heteromer. In addition, active substances can influence the aggregation status of receptors. The ligand-induced change in the receptor tertiary structure can affect the receptor-receptor affinity and can thereby promote association or dissociation of receptors or protomers. The antidepressants desipramine and citalopram promote the heteromerization of Sst5 - with dopamine D2 receptors , although the underlying mechanism remains unknown as these active ingredients are not classic binding partners of these receptors. In the example mentioned, the signal pathways also change with a changed degree of aggregation.

Individual evidence

  1. ↑ JD Urban et al: Functional selectivity and classical concepts of quantitative pharmacology. In: Journal of Pharmacology and Experimental Therapeutics . 320 (1) 2007, pp. 1-13. PMID 16803859 .
  2. ↑ T. Kenakin: Functional selectivity through protean and biased agonism: who steers the ship? In: Molecular Pharmacology . 72 (6) 2007, pp. 1393-1401. PMID 17901198 .
  3. ^ R. Rozenfeld, LA Devi: Exploring a role for heteromerization in GPCR signaling specificity . In: Biochem J . tape 433 , no. 1 , 2011, p. 11–18 , doi : 10.1042 / BJ20100458 , PMID 21158738 , PMC 3115900 (free full text).
  4. ^ J. González-Maeso, SC Sealfon: Functional selectivity in GPCR heterocomplexes. In: Mini-Rev Med Chem . Volume 12, 2012, p. 851. PMID 22681249 .
  5. ↑ JL Moreno et al .: Identification of Three Residues Essential for 5-Hydroxytryptamine 2A-Metabotropic Glutamate 2 (5-HT2A • mGlu2) Receptor Heteromerization and Its Psychoactive Behavioral Function. In: J Biol Chem . Volume 287, 2012, p. 44301. PMID 23129762 .
  6. ↑ JL Moreno, T. Holloway, L. Albizu; SC Sealfon, J. González-Maeso: Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists . In: Neurosci. Lett. tape 493 , no. 3 , 2011, p. 76–79 , doi : 10.1016 / j.neulet.2011.01.046 , PMID 21276828 , PMC 3064746 (free full text).
  7. ↑ I. Raote, A. Bhattacharya, Panicker MM: serotonin 2A (5-HT2A) Receptor Function: Ligand-Dependent Mechanisms and Pathways. In: A. Chattopadhyay (Ed.): Serotonin Receptors in Neurobiology. CRC Press, 2007, Chapter 6. PMID 21204452
  8. ↑ J. González-Maeso, RL Ang, T. Yuen et al .: Identification of a serotonin / glutamate receptor complex implicated in psychosis . In: Nature . tape 452 , no. 7183 , 2008, p. 93-97 , doi : 10.1038 / nature06612 , PMID 18297054 , PMC 2743172 (free full text).
  9. ↑ J. González-Maeso et al: Hallucinogens recruit specific cortical 5-HT (2A) receptor-mediated signaling pathways to affect behavior. In: Neuron. Volume 53, 2007, p. 439. PMID 17270739 .
  10. ↑ K. Szafran, S. Lukasiewicz, A. Faron-Górecka et al: Antidepressant drugs promote the heterodimerization of the dopamine D2 and somatostatin Sst5 receptors - fluorescence in vitro studies . In: Pharmacol Rep . tape 64 , no. 5 , 2012, p. 1253-1258 , PMID 23238481 .

literature

  • S. Maudsley, SA Patel, SS Park, LM Luttrell, B. Martin: Functional signaling biases in G protein-coupled receptors: Game Theory and receptor dynamics. In: Mini Rev Med Chem. Volume 12, 2012, p. 831. PMID 22681251
  • E. Goupil, SA Laporte, TE Hébert: Functional selectivity in GPCR signaling: understanding the full spectrum of receptor conformations. In: Mini Rev Med Chem. Volume 12, 2012, p. 817. PMID 22681252
  • GJ Digby, PJ Conn, CW Lindsley: Orthosteric- and allosteric-induced ligand-directed trafficking at GPCRs. In: Curr Opin Drug Discov Devel. Volume 13, 2010, p. 587. PMID 20812150