PHARMACOLOGY FACULTY
Selected Publications
  • Rowan MP, Berg KA, Milam SB, Jeske NA, Roberts JL, Hargreaves KM and Clarke WP (2010) 17β-Estradiol rapidly enhances bradykinin signaling in primary sensory neurons in vitro and in vivo. J Pharmacol Exp Ther 335:190-196.
  • Rowan MP, Ruparel NB, Patwardhan AM, Berg KA, Clarke WP and Hargreaves KM (2009) Peripheral delta opioid receptors require priming for functional competence in vivo. Eur J Pharmacol 602:283-287.
  • Berg KA and Clarke WP (2009) Functional selectivity at serotonin receptors, in Functional Selectivity of G Protein-Coupled Receptor Ligands:  New Opportunities for Drug Discovery (Neve KA ed) pp 155-176, The Humana Press, Totowa, NJ.
  • Berg KA, Dunlop J, Sanchez T, Silva M and Clarke WP (2008) A conservative, single-amino acid substitution in the second cytoplasmic domain of the human Serotonin2C receptor alters both ligand-dependent and -independent receptor signaling. J Pharmacol Exp Ther 324:1084-1092.
  • Berg KA, Clarke WP, Cunningham KA and Spampinato U (2008) Fine-tuning serotonin2c receptor function in the brain: molecular and functional implications. Neuropharmacology 55:969-976.
  • Aloyo VJ, Berg KA, Spampinato U, Clarke WP and Harvey JA (2008{in press}) Current status of inverse agonism at serotonin2A (5-HT2A) and 5-HT2C receptors. Pharmacol. Therap.
  • Berg KA, Harvey JA, Spampinato U and Clarke WP (2008) Physiological and therapeutic relevance of constitutive activity of 5 HT2A and 5 HT2C receptors for the treatment of depression, in Serotonin-Dopamine Interaction: Experimental Evidence and Therapeutic Relevance (Di Giovanni G, Esposito E and Di Matteo V eds), Elsevier, New York.
  • Berg KA, Dunlop J, Sanchez T, Silva M and Clarke WP (2008) A conservative, single-amino acid substitution in the second cytoplasmic domain of the human Serotonin2C receptor alters both ligand-dependent and -independent receptor signaling. J Pharmacol Exp Ther 324:1084-1092. PMID: 18065501
William P. Clarke
 

William P. Clarke

Professor of Pharmacology
Distinguished Teaching Professor
Ph.D., Wayne State University School of Medicine

Office: 210-567-4171
Email: clarkew@uthscsa.edu

 

View video introduction to Dr. Clarke's lab

 
Principles of Pharmacology Course Website
 

Keywords

serotonin, opioids, estrogen, G protein coupled receptors, schizophrenia, depression, anxiety, pain, functional selectivity, constitutive receptor activity, receptor theory

 

Research Summary

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.


• Lab Personnel •

Dr. Kelly Berg - Associate Professor/Research

Dr. Laura Sullivan - Postdoctoral Fellow

Teresa Chavera - Senior Research Associate

Peter LoCoco - Graduate Student (Co-mentored by Susan Mooberry, Ph.D.)

Blaine McGuire - Graduate Student

Raehannah Jamshidi - Graduate Student