Office: 210-567-4171
Email: clarkew@uthscsa.edu
Work in my lab centers on questions concerning the molecular nature of drug efficacy and the cellular mechanisms by which efficacy can be regulated. An understanding of the nature of drug efficacy and the factors by which it is regulated is essential for the design of rational treatment regimens in clinical situations. Drug efficacy is defined as the ability of a drug to produce a response. According to traditional receptor theory (see equation #1), the magnitude of an effect (E) produced when an agonist at a specified concentration ([A]) and interacts with a receptor is a function (ƒ) of the stimulus (S) produced by the agonist and depends upon 4 factors. Two of these are chemical properties of the agonist itself unique for each ligand-receptor pair; the affinity related parameter, KA, and "intrinsic efficacy" ε (ε describes the capacity of a drug to produce a receptor "stimulus" {which can be thought of as a conformational change in the receptor} which is transmitted to the signal transduction components of the cell). The remaining two parameters are cell or tissue dependent properties; receptor density, RT and a function, ƒ, that describes the efficiency of signal transduction. Thus, cellular mechanisms that influence drug efficacy are those that regulate any or all of these four parameters.
Equation #1
The drug property, intrinsic efficacy, according to traditional receptor theory, is a unique for each drug-receptor pair and is independent of the response measured. Thus, if a drug produced a 50% response (relative to that of a reference drug) for one measure, it must also produce a 50% response for all measures coupled to a receptor. Recent evidence from our laboratory, and others, challenges that assertion. Work in our lab has centered upon understanding the mechanisms by which drug intrinsic efficacy is response-dependent. Our working hypothesis is that drugs can elicit unique spectra of receptor conformations that have differential capacities to activate signaling mechanisms in cells.
Current models of receptor function are based on the existence of receptors in equilibrium between multiple conformations or states that display differential degrees of activity toward cellular signaling mechanisms in the absence of a ligand. One consequence of which is that receptors can activate signaling mechanisms in cells in the absence of a ligand (constitutive receptor activity) and some drugs have the capacity to turn off, as well as turn on, receptors. Drugs that reduce constitutive receptor activity are called inverse agonists and are said to have negative intrinsic efficacy. Work in our lab has been devoted to understanding the physiological and pharmacological consequences of inverse agonism and how it can be regulated.
Cellular factors involved in the regulation of drug efficacy that are under investigation include the consequences of activation of other receptor systems on cells (so-called "cross-talk" between receptor systems) and mechanisms of desensitization (homologous and heterologous). Furthermore, the impact of subcellular localization of receptors and signaling molecules with respect to membrane microdomains on drug efficacy is also under study.
Selected Publications
Berg, K.A., Evans, K.L.J., Cropper, J.D. and Clarke, W.P. Temporal regulation of agonist efficacy at 5-HT1A and 5-HT1B receptors. J. Pharmacol Exp Ther 302:957-962, 2002.
Berg KA, Clarke WP. Regulation of 5-HT(1A) and 5-HT(1B) receptor systems by phospholipid signaling cascades. Brain Res Bull. 2001 Nov 15;56(5):471-7. Review.
Berg KA, Stout BD, Maayani S, Clarke WP. Differences in rapid desensitization of 5-hydroxytryptamine2A and 5-hydroxytryptamine2C receptor-mediated phospholipase C activation. J Pharmacol Exp Ther. 2001 Nov;299(2):593-602.
Berg KA, Cropper JD, Niswender CM, Sanders-Bush E, Emeson RB, Clarke WP. RNA-editing of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity. Br J Pharmacol. 2001 Sep;134(2):386-92.
Evans KL, Cropper JD, Berg KA, Clarke WP. Mechanisms of regulation of agonist efficacy at the 5-HT(1A) receptor by phospholipid-derived signaling components. J Pharmacol Exp Ther. 2001 Jun;297(3):1025-35.
Clarke, W.P. and R.A. Bond. The elusive nature of intrinsic efficacy. Trends Pharmacol. Sci. 19: 270-276, 1988.
