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. |
| Date |
Description |
Institution |
# Students |
| 6/2012 - Present |
Membership on Supervising Committee |
The University of Texas Health Science Center at San Antonio |
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| 7/2011 - Present |
Ph.D. Dissertations Directed |
The University of Texas Health Science Center at San Antonio |
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| 6/2011 - Present |
Ph.D. Dissertations Directed |
The University of Texas Health Science Center at San Antonio |
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| 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 |
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| 6/2008 - Present |
Receptors-Effectors (Summer Undergraduate Course) |
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| 1/2007 - Present |
Membership on Supervising Committee |
The University of Texas Health Science Center at San Antonio |
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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).
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| 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).
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| 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).
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| 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).
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| 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).
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| 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).
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| 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).
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| 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).
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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.
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| Sullivan LC, Clarke WP, Berg KA. Atypical antipsychotics and inverse agonism at 5-HT2 receptors Curr Pharm Des 2015 Jan;21(26):3732-3738.
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| 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.
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| 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.
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Federal |
| Funding Agency |
ASPET |
| Title |
ASPET Fellowship Program for Undergraduate Students |
| Status |
Active |
| Period |
6/2007 - Present |
| Role |
Principal Investigator |
| Grant Detail |
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| 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. |
