William P. Clarke
Professor of Pharmacology
Distinguished Teaching Professor
Ph.D., Wayne State University School of Medicine
serotonin, opioids, estrogen, G protein coupled receptors, schizophrenia, depression, anxiety, pain, functional selectivity, constitutive receptor activity, receptor theory
Pharmacology is the study of drug action on biological systems. In science, drugs are used for two major purposes; for the treatment of disease in medicine and as research tools in the laboratory to decipher how physiological and cellular systems work. Consequently, understanding how drugs interact with receptors has important implications in both medicine and research. The main focus of our laboratory is to understand the nature, and the regulation of, drug-receptor interactions that are responsible for production of a response (efficacy). We work almost exclusively with 7 transmembrane-spanning receptors (G protein coupled receptors) and have several research projects that involve serotonin (schizophrenia, affective disorders), opioid, bradykinin and prostaglandin receptors (pain). We are especially interested in studying constitutive receptor activity and functional selectivity of drugs; two relatively new concepts in receptor theory.
Rather than existing as quiescent molecules that require the binding of a ligand to produce activation and a response, receptors can become active spontaneously (constitutively active). We are interested in learning why some receptors are more constitutively active than others, how constitutive activity is regulated by cells, why constitutive activity of the same receptor is different in different cells (different tissues and brain regions for example) and at different times (different physiological conditions), and the pathophysiological relevance of constitutive receptor activity.
For many years we have known that receptors can regulate the activity of more than one signaling pathway within cells. Over the past several years, our lab has been accumulating evidence which demonstrates that different drugs, acting at the same receptor, can differentially regulate these multiple signaling pathways. This type of drug action is called 'functional selectivity', but has been referred to in the literature as "agonist-directed trafficking of receptor stimulus", "biased agonism", and "stimulus trafficking" among others. Thus, drugs have more selectivity than that afforded by differential binding to different receptor subtypes. Functional selectivity can perhaps explain why some drugs are effective at treating a disease while others are not even though they act at the same receptor. Functional selectivity heralds a new era in drug development where drugs acting at a single receptor subtype can be developed that maximize therapeutic, and minimize adverse, effects. Our work in this area involves studies to identify the mechanisms by which drugs selectively regulate cellular signaling pathways, to learn how functional selectivity can be regulated (cell/tissue phenotype- and physiological state-dependence), and to understand the physiological effects of functionally selective drugs and how they can be exploited to improve therapeutic efficacy and selectivity.