Medical brain Notes 3

  G protein-coupled receptors G protein-coupled receptors (GPCR) represent the largest group among the receptors of both hormones and neuro-transmitters, and accordingly have a prominent role as drug targets. The percentage of all drugs in use today that act on one or the other GPCR is given in the literature as 25-50%, and it is likely to increase in the future 1 . Examples are:   •       Muscarinic acetylcholine receptors (several types)   •       Catecholamine receptors   •       Serotonin receptors 5-HT  1,2,4,6   •       GABA B  receptor   •       `Metabotropic' glutamate receptors (11 subtypes)   •       Purine receptors (P2Y): Adenosine, AMP, ADP, ATP   •       Peptide hormone receptors   As noted before, most of the presently used drugs target receptors...

  Structure and function of G protein-coupled receptors G protein-coupled receptors all belong to one structural family, which is frequently referred to as the `7-TM' receptor family. This name refers to the 7  α -helical transmem-brane domains, which occur in all of these molecules. Vari-ability is larger in the N-terminal and C-terminal parts and the loops intervening between the transmembrane domains, which are exposed to the extracellular and the cytoplasmic spaces, respectively.   The basic mode of action of a G protein coupled receptor and the G protein activated by it is illustrated in Figure 8.1. Binding of the agonist to the extracellular face of the recep-tor triggers a conformational change that is communicated to the intracellular portion of the receptor and there is re-layed to the G protein. The latter is a trimer, comprised of one  α ,  β  and  γ  subunit each. The  β  and  γ  subunits remain associated throughou...

  The complexity of G protein signalling Although it is usually pointless to point out the complexity of biological systems, here it may be appropriate. G protein coupled receptors, besides their roles in respond-ing to intrinsic signals (hormones and transmitters), are also responsible for our ability to smell and taste, which means that G protein-coupled receptors respond to extrinsic rather than intrinsic signals. Beyond the large number of recep-tors with known roles, there is an even larger number of so-called `orphan' receptors, the ligands and functional roles of which have not yet been determined. The overall number of GPCR genes in the human genome is at least 300-400 – which corresponds to about 1% of all genes. As pointed out above, the significance of G protein-coupled receptors in pharmacology is already great today, and it is likely to increase as more information on the ligands and functional roles of individual receptors will become avail-able, and the interaction o...

  Agonist-specific coupling On the other hand, receptors may be promiscuous as well and couple to more than one G protein. Many receptors appear to be pre-associated with G proteins in the absence of agonists. The pre-bound G protein may in turn change the conformation of the entire receptor and thus modify its affinity for mediator and drug molecules. If there is more than one type of G protein to couple to a given receptor, this may result in several sub-populations of the receptor that may exhibit diverging affinities for different agonists. This behaviour is known as `agonist-specific coupling'.   An example of agonist-specific coupling is shown in Fig-ure 8.3. The receptor in question is the  α 1A -adrenergic re-ceptor. This receptor triggers at least two different intracel-lular signaling pathways: Arachidonic acid is released by phospholipase A 2 , and inositoltriphosphate (IP 3 ) is released by phospholipase C. These two effects are mediated by two different G pro...

  GPCR oligomerization Another source of variation is the oligomeric state of G protein-coupled receptors. In Figure 8.1, the receptor is depicted as a monomeric molecule, and indeed this was the prevailing model until fairly recently. However, it is now clear that very many GPCR are indeed oligomeric. This has several consequences:   •       Efficacy and potency of a ligand may be different for monomeric and oligomeric receptors.   •       Dose-effect curves may take different shapes, due to cooperative ligand binding 4 .   •       Oligomers may be `homomers' but also `heteromers', which means that they may form from like or from dif ferent subunits. The existence of heteromers adds an-other dimension to the variability of receptor types, sim-ilar as with the voltage-gated potassium channels cov-ered earlier.   •       It is possible to develop multivalent drugs ...

  'Allosteric' GPCR agonists and antagonists While most drugs that act as agonists or agonists of GPCR appear to bind competitively, i.e. to the binding site of the physiological agonist, several compounds have been report-ed to bind to other sites, allowing them to bind simultaneously with the physiological agonist. Binding of such `al-losteric' effectors may promote or reduce activation by the physiological agonist without actually causing any effect in the absence of the latter. As an example, the interaction of two molecules with A 1  adenosine receptors 5  is shown in Figure 8.5. While the `allosteric' molecule in question (PD 81,723) does indeed enhance binding of the agonist (cyclohexyladenosine) at intermediate concentrations, it actually inhibits it at higher concentrations, which is not at all in keeping with the expectations for a true allosteric effector. An alternative interpretation is that the A1 adenosine receptor is oligomeric, and that cyclohexyladenos...