Agonist-specific receptor conformations

I agree entirely with Dr Tuc ek with respect to the idea that the pharmacological world of agonism cannot be accommodated by a single receptor active state. The concept that receptor proteins traverse an energy landscape to adopt a number of conformations and that different agonists select different spectra of conformations is one possibility[1xKenakin, T.P. Trends Pharmacol. Sci. 1995; 16: 232–238Abstract | Full Text PDF | PubMed | Scopus (491)See all References, 2xKenakin, T.P. Trends Pharmacol. Sci. 1996; 17: 190–191Abstract | Full Text PDF | Scopus (66)See all References]. There is now evidence to show that some agonists `traffic' stimulus to different G proteins; this may be the next frontier for agonist selectivity in therapeutics. There is a theoretical rationale[3xKenakin, T.P. Ann. New York Acad. Sci. 1997; 812: 116–125Crossref | PubMed | Scopus (24)See all References[3]linked to experimental findings[4xChidiac, P., Nouet, S., and Bouvier, M. Mol. Pharmacol. 1996; 50: 662–669PubMedSee all References[4] to indicate that different setpoints of receptor systems can unveil agonist-selective receptor-active states. There are also more direct data to show that different agonists produce different receptor-active states[5xKrumins, A.M. and Barber, R. Mol. Pharmacol. 1997; 52: 144–153PubMedSee all References[5]. Finally, there are indi- cations that ligands may induce conformations that do not reveal their presence by a physiological response, but in other ways. For example, the CCK receptor antagonist d-Tyr-Gly[(Nle28,31,DTrp30)- cholecystokinin-26–32] phenylethyl ester, does not produce an acute physiological response (positive or negative), but nevertheless does accelerate CCK receptor internalization. This effect is consistent with the production of a conformation by li-gand binding that directs the receptor into the clathrin-dependent endocytotic pathway[6xRoettger, B.F. et al. Mol. Pharmacol. 1997; 51: 357–362PubMedSee all References[6].So where does this leave us modellers who try to reduce the world to minimal numbers of variables? While the cubic ternary complex model[7xWeiss, J.M., Morgan, P.H., Lutz, M.W., and Kenakin, T.P. J. Theor. Biol. 1996; 178: 151–167Crossref | Scopus (137)See all References, 8xWeiss, J.M., Morgan, P.H., Lutz, M.W., and Kenakin, T.P. J. Theor. Biol. 1996; 178: 169–182Crossref | Scopus (79)See all References]is a statistically complete version of the extended ternary complex model, it already is heuristic and essentially not useful for fitting purposes. Although the computer program can accommodate up to three different G proteins (see Fig. 5 of [7xWeiss, J.M., Morgan, P.H., Lutz, M.W., and Kenakin, T.P. J. Theor. Biol. 1996; 178: 151–167Crossref | Scopus (137)See all References[7]) and therefore can handle three different activation reactivities, this leads to systems where it is difficult to visualize what is happening in the Euclidean space. More importantly, such models result in a plethora of unverifiable constants. Any number of receptor states (see [9xVogel, W.K., Mosser, V.A., Bulesco, D.A., and Schimerlik, M.I. J. Biol. Chem. 1995; 270: 1485–15493Crossref | PubMed | Scopus (90)See all References[9]) can be built into the ternary complex model and this leads to a bewildering array of possible interconversions. However, such models quickly lose their ability to be effectively predictive of pharmacological receptor behaviour. In the end, if a model is to be useful and predictive, Occam's razor must be applied and when the model fails to describe the experiment, then grudgingly, new pieces must be added. However, for agonist-selective states, it is difficult to see how conventional models will be useful because agonist-specific phenomena will cease to be consistent with unique sets of parameter values.Perhaps a better interpretation of the energy landscape spectrum for receptors can be obtained from Onaran and Costa's `unitary probabilistic view of allosteric transition'[10xOnaran, H.O. and Costa, T. Ann. New York Acad. Sci. 1997; 812: 98–115Crossref | PubMed | Scopus (61)See all References[10]. Here, a spectrum of conformations is predicted and agonists, by selective affinity for the different conformations, redistribute these conformations. From this standpoint, the histograms describing stimulus trafficking[2xKenakin, T.P. Trends Pharmacol. Sci. 1996; 17: 190–191Abstract | Full Text PDF | Scopus (66)See all References[2]might be better visualized as shown in Fig. 1Fig. 1. As agonists interact with the system, different receptor-active states are enriched and this leads to different signalling to G proteins. Thus, models rooted in statistics of probability and not conventional equilibrium kinetics may hold the key to moving this branch of receptor pharmacology forward. I view such a prospect as exciting and look forward to applications of new mathematical techniques to older pharmacological problems.Fig. 1A frequency distribution of a range of receptor conformations. Three shaded bars represent three `active' receptor states (I, II, III) that can activate G proteins. In the absence of ligands, the relative abundance of these states is low. Agonist A shifts the frequency distributions of all the conformations and enriches states II and III, while agonist B produces another distribution enriching state I.View Large Image | Download PowerPoint Slide