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Clarke, William P

Graduate School of Biomedical Sciences
Pharmacology
(210) 567-4171
clarkew@uthscsa.edu

Appointments Education Expertise Teaching Publications Grants

9/2008 - Present

Professor

The University of Texas Health Science Center at San Antonio, Pharmacology, San Antonio, TX

Drug efficacy

- Work in my lab centers on questions concerning the molecular nature of drug efficacy and the cellular mechanisms by which efficacy can be regulated. Drug efficacy is defined as the ability of a drug to produce a response or an effect. According to traditional receptor theory (see equation #1), the magnitude of an effect (E) produced when an agonist at a specified concentration ([A]) interacts with a receptor is a function (?) 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, Kd and ?intrinsic efficacy?, e (e 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 an undefined function, ? (typically a hyperbola {S/(S+a)}), 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 Brain slices and cell culture (primary and cell lines) systems are used as models for our studies along with some in/ex vivo studies. Cellular consequences of receptor activation (i.e. ?response?) are studied using a multifaceted approach including biochemical (receptor binding, quantitative receptor autoradiography, immunocytochemistry, enzyme activity assays, measurement of 2nd messenger levels [cAMP, phosphoinositides, calcium, arachidonic acid], protein phosphorylation, etc.), molecular (heterologous expression, site-directed mutagenesis, chimera, baculovirus etc.) and imaging (fluorescence, FRET) techniques. 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). Since single receptor subtypes typically couple to multiple effector pathways in cells, we are especially interested in effector pathway-dependent efficacy and its differential regulation. With the recent discovery that G protein coupled receptor systems display constitutive activity (in the absence of an activating ligand) and the existence of ligands with negative intrinsic efficacy (i.e. ?inverse agonists?), we are studying properties of inverse agonists. 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.

Abstract

LoCoco PM, Risinger AL, Mooberry SL, Berg KA, Clarke WP. The neuroprotective agent, P7C3-A20, prevents paclitaxel-induced allodynia in the rat; 2015 Nov. (Presented at the Society for Neuroscience Meeting).

LoCoco PM, Chavera TA, Scofield HO, Jamshidi RJ, Mooberry SL, Berg KA, Clarke WP. Subpopulations of peripheral sensory neurons are differentially sensitive to the microtubule-targeting agent, paclitaxel; 2015 Jan. (Presented at the Chemotherapy-Induced Peripheral Neuropathy Symposium, Santa Barbara, CA).

LoCoco PM, Chavera TA, Scofield HO, Jamshidi RJ, Mooberry SL, Berg KA, Clarke WP. Subpopulations of peripheral sensory neurons are differentially sensitive to the microtubule-targeting agent, paclitaxel; 2014 Nov. (Presented at the Society for Neuroscience Meeting).

Sullivan LC, Jamshidi RJ, LoCoco PM, Berg KA, Clarke WP. Age-related differences in the sensitivity to allodynia produced by TRP receptor agonists; 2014 Nov. (Presented at the Society for Neuroscience Meeting).

McGuire BA, Chavera TA, Clarke WP, Berg KA. Allosteric interactions within delta opioid receptor ? kappa opioid receptor (DOR-KOR) heteromers in peripheral sensory neurons; 2014 Nov. (Presented at the Experimental Biology Meeting, San Diego, CA).

LoCoco PM, Villarreal G, Dybdal-Hargreaves NF, Mooberry SL, Berg KA, Clarke WP. The neuroprotective agent, P7C3-A20, prevents paclitaxel-induced peripheral neuropathy in the rat; 2014 Oct. (Presented at UTHSCSA Pharmacology/Neuroscience Graduate Student Symposium).

Jamshidi RJ, McGuire BA, Sullivan LC, Chavera TA, Clarke WP, Berg KA. Unique regulation of peripheral kappa opioid receptor (KOR) function by the protean ligand, norBNI; 2014 Mar. (Presented at the Behavior, Biology, and Chemistry Conference, San Antonio, TX).

LoCoco PM, Scofield HO, Chavera TA, Mooberry SL, Berg KA, Clarke WP. The microtubule-targeting agent, paclitaxel, differentially damages bradykinin (B2) receptor-expressing nociceptors San Antonio TX; 2013 Oct. (Presented at UTHSCSA Pharmacology/Neuroscience Graduate Student Symposium).

LoCoco PM, Scofield HO, Chavera TA, Mooberry SL, Berg KA, Clarke WP. Bradykinin (B2) receptor- expressing nociceptors are differentially sensitive to the microtubule-targeting agent, paclitaxel; 2013 Jan. (Presented at Translational Research CTSA Consortium).

Jamshidi RJ, McGuire BA, Sullivan LC, Chavera TA, Clarke WP, Berg KA. Long-Term Regulation of Kappa Opioid Receptor (KOR) Function in Peripheral Sensory Neurons In Vivo and Ex Vivo; 2013 Jan. (Presented at the Terry M. Mikiten Graduate Student Research Forum., San Antonio, TX).

Journal Article

Sullivan LC, Chavera TA, Jamshidi RJ, Berg KA, Clarke WP. Constitutive desensitization of opioid receptors in peripheral sensory neurons J Pharmacol Exp Ther 2016 Jan;359(3):411-419.

Sullivan LC, Clarke WP, Berg KA. Atypical antipsychotics and inverse agonism at 5-HT2 receptors Curr Pharm Des 2015 Jan;21(26):3732-3738.

Rowan MP, Berg KA, Roberts JL, Hargreaves KM, Clarke WP. Activation of estrogen receptor alpha enhances bradykinin signaling in peripheral sensory neurons of female rats J Pharmacol Exp Ther 2014 Jan;349(3):526-532.

Broselid S, Berg KA, Chavera TA, Kahn R, Clarke WP, Olde B, Leeb-Lundberg LM. G protein-coupled receptor 30 (GPR30) forms a plasma membrane complex with membrane-associated guanylate kinases (MAGUKs) and protein kinase A-anchoring protein 5 (AKAP5) that constitutively inhibits cAMP production J Biol Chem 2014 Jan;289(32):22117-22127.

Clarke WP, Chavera, TA, Silva M, Sullivan LC, Berg KA. Signalling profile differences: paliperidone versus risperidone Br J Pharmacol 2013 Jan;170(3):532-545.

Federal
Funding Agency	ASPET
Title	ASPET Fellowship Program for Undergraduate Students
Status	Active
Period	6/2007 - Present
Role	Principal Investigator
Grant Detail
Funding Agency	NIH/NIA
Title	Aging, peripheral pain and analgesia
Status	Active
Period	2/2015 - 1/2018
Role	Principal Investigator
Grant Detail	We propose to evaluate the effect of aging on the function and regulation of peripheral, pain-sensing neurons and opioid receptor systems expressed by these neurons. Our ultimate goal is to develop analgesics with improved efficacy and safety for use in the elderly population
Funding Agency	NIH/NGMS
Title	Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia
Status	Active
Period	1/2014 - 11/2017
Role	Principal Investigator
Grant Detail	The major goal of this project is to study the regulation of kappa opioid receptor (KOR) signaling systems by the MAPKinases, ERK and JNK, as well as acute desensitization of KOR agonist signaling in peripheral sensory neurons, using primary cultures of adult rat sensory neurons and a behavioral model of nociception
Funding Agency	NIH/NIDA
Title	Regulation of DOR-KOR heteromer formation in pain-sensing neurons
Status	Active
Period	9/2014 - 8/2017
Role	Principal Investigator
Grant Detail	We propose to validate approaches to disrupt the formation or function of delta-kappa opioid receptor heteromers expressed by pain-sensing neurons in vivo and ex vivo.
Funding Agency	NIH/IIMS-CTRC Pilot Award
Title	Efficacy of P7C3-A20 to prevent pain symptoms of chemotherapy-induced peripheral neuropathy
Status	Active
Period	5/2015 - 4/2016
Role	Principal Investigator
Grant Detail	In this pilot project, we will focus on pain behavioral assays (measuring changes in three different pain modalities) to assess if a novel neuroprotective agent, P7C3-A20, is effective against development of signs of CIPN. We will test the hypothesis that P7C3-A20 prevents development of signs of CIPN (pain) in rats produced by treatment with paclitaxel, vincristine, oxaliplatin, and bortezomib. These drugs are prototypical members of different classes of anticancer drugs with different mechanisms of anticancer action, but all produce painful peripheral neuropathy. Protection of peripheral pain-sensing neurons from damage will be evaluated using behavioral pain assays (thermal heat, thermal cold and mechanical allodynia)
Funding Agency	NIH/NIGMS
Title	Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia in female rats
Status	Active
Period	1/2014 - 11/2015
Role	Principal Investigator
Grant Detail	This is an administrative supplement to extend the study of regulation of kappa opioid receptor (KOR) signaling in peripheral sensory neurons to female rats. The goals of this project are to assess the antinociceptive effects of peripherally-restricted KOR agonists in female rats using behavioral assays of nociception and to assess the cellular signaling of KOR agonists in peripheral sensory neurons derived from female rats.
Private
Funding Agency	William and Ella Owens Medical Research Foundation
Title	Opioid receptor functional competence in peripheral sensory neurons
Status	Active
Period	1/2013 - 12/2015
Role	Principal Investigator
Grant Detail	The major goal of this project is to identify the COX and LOX metabolites that regulate the responsiveness of the opioid receptor systems in pain-sensing neurons (nociceptors)

Year	Degree	Discipline	Institution
1984	PhD	Physiology	Wayne State University School of Medicine Detroit , MI
1979	MS	Biology	Northeastern University Boston , MA
1974	BS	Chemistry	Boston College Boston , MA
	Postdoctoral Fellowship	Pharmacology	Mount Sinai School of Medicine New York , NY

Date	Description	Institution	# Students
6/2012 - Present	Membership on Supervising Committee	The University of Texas Health Science Center at San Antonio

7/2011 - Present	Ph.D. Dissertations Directed	The University of Texas Health Science Center at San Antonio

6/2011 - Present	Ph.D. Dissertations Directed	The University of Texas Health Science Center at San Antonio

7/2010 - Present	Post-Doctoral Student Supervision	The University of Texas Health Science Center at San Antonio

1/2010 - Present	Membership on Supervising Committee	The University of Texas Health Science Center at San Antonio

6/2008 - Present	Receptors-Effectors (Summer Undergraduate Course)

1/2007 - Present	Membership on Supervising Committee	The University of Texas Health Science Center at San Antonio

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Clarke, William P

Drug efficacy

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