P A Insel

University of California, San Diego, San Diego, California, United States

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Publications (424)2805.1 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cyclic AMP (cAMP), acting via protein kinase A (PKA), regulates many cellular responses but the role of mitochondria in such responses is poorly understood. To define such roles, we used quantitative proteomic analysis of mitochondria-enriched fractions and performed functional and morphologic studies of wild-type (WT) and kin- (PKA-null) murine S49 lymphoma cells. Basally, 75 proteins significantly differed in abundance between WT and kin- S49 cells. WT, but not kin-, S49 cells incubated with the cAMP analog 8-(4-Chlorophenylthio)adenosine cAMP (CPT-cAMP) for 16h have: a) increased expression of mitochondria-related genes and proteins, including ones in pathways of branched chain amino acid (BCAA) and fatty acid metabolism, and b) increased maximal capacity of respiration on branched chain keto acids and fatty acids. CPT-cAMP also regulates the cellular rate of ATP-utilization, as the rates of both ATP-linked respiration and proton efflux are decreased in WT but not kin- cells. CPT-cAMP protected WT S49 cells from glucose or glutamine deprivation, In contrast, CPT-cAMP did not protect kin- cells or WT cells treated with the PKA inhibitor H89 from glutamine deprivation. Under basal conditions, the mitochondrial structure of WT and kin- S49 cells is similar. Treatment with CPT-cAMP produced apoptotic changes (i.e., decreased mitochondrial density and size, and loss of cristae) in WT, but not kin-, cells. Together, these findings show that cAMP acts via PKA to regulate multiple aspects of mitochondrial function and structure. Mitochondrial perturbation thus likely contributes to cAMP/PKA-mediated cellular responses. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 07/2015; 290(36). DOI:10.1074/jbc.M115.658153 · 4.57 Impact Factor
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    ABSTRACT: In this Perspectives, former and current editors of Molecular Pharmacology together with the guest editors for this 50 year Anniversary Issue provide a historical overview of the Journal since its founding in 1965. The substantial impact the journal has had on the field of pharmacology as well as on biomedical science is discussed, as is the broad scope of the journal. The authors conclude that, true to the original goals for the Journal, Molecular Pharmacology today remains an ideal venue for work that provides a mechanistic understanding of drugs, molecular probes, and their biological targets. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 05/2015; 88(1). DOI:10.1124/mol.115.099564 · 4.13 Impact Factor
  • Aaron C Overland · Paul A Insel
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    ABSTRACT: Agonist stimulation of GPCRs can transactivate epidermal growth factor receptors (EGFRs) but the precise mechanisms for this transactivation have not been defined. Key to this process is the protease-mediated shedding of membrane-tethered ligands, which then activate EGFRs. The specific proteases and the events involved in GPCR-EGFR transactivation are not fully understood. We have tested the hypothesis that transactivation can occur by a membrane-delimited process: direct increase in the activity of membrane type-1 matrix metalloprotease (MMP14, MT1-MMP) by heterotrimeric G proteins and in turn, the generation of HB-EGF and activation of EGFR. Using membranes prepared from adult rat cardiac myocytes and fibroblasts, we found that MMP14 activity is increased by angiotensin II, phenylephrine, GTP and GTPγS. MMP14 activation by GTPγS occurs in a concentration and time-dependent manner, does not occur with GMP or ATPγS stimulation and is not blunted by inhibitors of Src, PKC, PLC, PI3K, or soluble MMPs. This activation is specific to MMP14, as it is inhibited by a specific MMP14 peptide inhibitor and siRNA knockdown. MMP14 activation by GTPγS is pertussis toxin-sensitive. A role for heterotrimeric G protein βγ subunits was shown by using the Gβγ inhibitor gallein and direct activation of recombinant MMP14 by purified βγ subunits. GTPγS-stimulated activation of MMP14 also results in membrane release of HB-EGF and activation of EGFR. These results define a previously unrecognized, membrane-delimited mechanism for EGFR transactivation via direct G protein activation of MMP14 and identify MMP14 as a heterotrimeric G-protein-regulated effector. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 03/2015; 290(16). DOI:10.1074/jbc.C115.647073 · 4.57 Impact Factor
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    ABSTRACT: G protein-coupled receptors (GPCRs), the largest family of signaling receptors in the human genome, are also the largest class of targets of approved drugs. Are the optimal GPCRs (in terms of efficacy and safety) currently targeted therapeutically? Especially given the large number (~120) of orphan GPCRs (which lack known physiologic agonists), it is likely that previously unrecognized, especially orphan, GPCRs regulate cell function and can be therapeutic targets. Knowledge is limited regarding the GPCRs expressed by native cells that are activated by endogenous ligands (endoGPCRs). Here, we review approaches to define their expression in tissues and cells and results from studies using these approaches. We identify problems with the available data and suggest future ways to identify and validate the physiologic and therapeutic roles of previously unrecognized GPCRs. We propose that a particularly useful approach to identify functionally important GPCRs with therapeutic potential will be to focus on receptors that show selective increases in expression in diseased cells from patients and experimental animals. The American Society for Pharmacology and Experimental Therapeutics.
    Molecular pharmacology 03/2015; 88(1). DOI:10.1124/mol.115.098129 · 4.13 Impact Factor
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    ABSTRACT: Objective The trigeminovascular system plays a central role in migraine, a condition in need of new treatments. The neuropeptide, calcitonin gene-related peptide (CGRP), is proposed as causative in migraine and is the subject of intensive drug discovery efforts. This study explores the expression and functionality of two CGRP receptor candidates in the sensory trigeminal system.Methods Receptor expression was determined using Taqman G protein-coupled receptor arrays and immunohistochemistry in trigeminal ganglia (TG) and the spinal trigeminal complex of the brainstem in rat and human. Receptor pharmacology was quantified using sensitive signaling assays in primary rat TG neurons.ResultsmRNA and histological expression analysis in rat and human samples revealed the presence of two CGRP-responsive receptors (AMY1: calcitonin receptor/receptor activity-modifying protein 1 [RAMP1]) and the CGRP receptor (calcitonin receptor-like receptor/RAMP1). In support of this finding, quantification of agonist and antagonist potencies revealed a dual population of functional CGRP-responsive receptors in primary rat TG neurons.InterpretationThe unexpected presence of a functional non-canonical CGRP receptor (AMY1) at neural sites important for craniofacial pain has important implications for targeting the CGRP axis in migraine.
    03/2015; 2(6). DOI:10.1002/acn3.197
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    ABSTRACT: The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c(+) cells (Gnas(ΔCD11c) mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by Gnas(ΔCD11c) DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.
    Proceedings of the National Academy of Sciences 01/2015; 112(5). DOI:10.1073/pnas.1417972112 · 9.67 Impact Factor
  • Paul A Insel · Susan G Amara · Terrence F Blaschke
    Annual Review of Pharmacology 01/2015; 55(1):11-4. DOI:10.1146/annurev-pharmtox-101714-123102 · 18.37 Impact Factor
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    ABSTRACT: Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is an effector of cAMP signaling and has been implicated to have roles in numerous diseases, including diabetes mellitus, heart failure, and cancer. We used a computational molecular modeling approach to predict potential binding sites for allosteric modulators of Epac and to identify molecules that might bind to these regions. This approach revealed that the conserved hinge region of the cyclic nucleotide-binding domain of Epac1 is a potentially druggable region of the protein. Using a bioluminescence resonance energy transfer-based assay (CAMYEL, cAMP sensor using YFP-Epac-Rluc), we assessed the predicted compounds for their ability to bind Epac and modulate its activity. We identified a thiobarbituric acid derivative, 5376753, that allosterically inhibits Epac activity and used Swiss 3T3 and HEK293 cells to test the ability of this compound to modulate the activity of Epac and PKA, as determined by Rap1 activity and vasodilator-stimulated phosphoprotein phosphorylation, respectively. Compound 5376753 selectively inhibited Epac in biochemical and cell migration studies. These results document the utility of a computational approach to identify a domain for allosteric regulation of Epac and a novel compound that prevents the activation of Epac1 by cAMP.
    Journal of Biological Chemistry 09/2014; 289(42). DOI:10.1074/jbc.M114.569319 · 4.57 Impact Factor
  • P A Insel · A Wilderman · L Zhang · M M Keshwani · A C Zambon
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    ABSTRACT: Increases in cyclic AMP (cAMP) are pro-apoptotic in numerous cell types, but the mechanisms of cAMP-promoted apoptosis are poorly defined. We have used murine S49 T-lymphoma cells as a model to provide insight into these mechanisms. Increases in cAMP in wild-type (WT) S49 cells were first noted to kill these cells in the 1970 s, but only in recent years, it was shown that this occurs by the intrinsic (mitochondria-dependent) apoptotic pathway. The apoptotic response does not occur in protein kinase A-null (kin-) clonal variants of WT S49 cells and thus is mediated by protein kinase A (PKA). A second S49 clonal variant, cAMP-Deathless (D-), has PKA activity but lacks cAMP-promoted apoptosis. Apoptosis in WT S49 cells occurs many hours after cAMP/PKA-promoted G1 cell cycle arrest and involves increased expression of Bim, a pro-apoptotic member of the Bcl-2 (B-cell lymphoma-2) family. This increase in Bim expression does not occur in kin- or D- S49 cells and knockdown of Bim blunts cAMP-mediated apoptosis in WT cells. Cytotoxic T lymphocyte antigen-2 also appears to contribute to cAMP/PKA-promoted apoptosis of S49 cells. Based on time-dependent differences in gene expression between WT, D- and kin- S49 cells following incubation with 8-(4-chlorophenylthio)-cAMP, additional genes and proteins are likely involved in this apoptosis. Studies with S49 cells should reveal further insight regarding the mechanisms of cAMP/PKA-promoted cell death, including the identification of proteins that are targets to enhance (e. g., in cancer) or inhibit (e. g., cardiac failure) apoptosis in response to hormones, neurotransmitters, and drugs.
    Hormone and Metabolic Research 07/2014; 46(12). DOI:10.1055/s-0034-1384519 · 2.12 Impact Factor
  • AJP Cell Physiology 07/2014; 307(7). DOI:10.1152/ajpcell.00221.2014 · 3.78 Impact Factor
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    ABSTRACT: Caveolae, flask-like invaginations of the plasma membrane, were discovered nearly 60 years ago. Originally regarded as fixation artifacts of electron microscopy, the functional role for these structures has taken decades to unravel. The discovery of the caveolin protein in 1992 (by the late Richard G.W. Anderson) accelerated progress in defining the contribution of caveolae to cellular physiology and pathophysiology. The three isoforms of caveolin (caveolin-1, -2, and -3) are caveolae-resident structural and scaffolding proteins that are critical for the formation of caveolae and their localization of signaling entities. A PubMed search for "caveolae" reveals ∼280 publications from their discovery in the 1950s to the early 1990s, whereas a search for "caveolae or caveolin" after 1990, identifies ∼7000 entries. Most work on the regulation of biological responses by caveolae and caveolin since 1990 has focused on caveolae as plasma membrane microdomains and the function of caveolin proteins at the plasma membrane. By contrast, our recent work and that of others has explored the localization of caveolins in multiple cellular membrane compartments and in the regulation of intracellular signaling. Cellular organelles that contain caveolin include mitochondria, nuclei and the endoplasmic reticulum. Such intracellular localization allows for a complexity of responses to extracellular stimuli by caveolin and the possibility of novel organelle-targeted therapeutics. This review focuses on the impact of intracellular localization of caveolin on signal transduction and cell regulation.-Fridolfsson, H. N., Roth, D. M., Insel, P. A., Patel, H. P. Regulation of intracellular signaling and function by caveolin.
    The FASEB Journal 05/2014; DOI:10.1096/fj.14-252320 · 5.04 Impact Factor
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    ABSTRACT: The signaling molecule cAMP primarily mediates its effects by activating PKA and/or Epac. Epac has been implicated in many responses in cells but its precise roles have been difficult to define in the absence of Epac inhibitors. Epac, a guanine nucleotide exchange factor for the low molecular weight G protein Rap, is directly activated by cAMP. Using a BRET-based assay (CAMYEL) to examine modulators of Epac activity, we took advantage of its intramolecular movement that occurs upon cAMP binding to assess Epac activation. We found that the use of CAMYEL can detect the binding of cAMP analogs to Epac and their modulation of its activity and can distinguish between agonists (cAMP), partial agonists (8-CPT-cAMP), and super-agonists (8-CPT-2'-O-Me-cAMP). The CAMYEL assay can also identify competitive and uncompetitive Epac inhibitors, e.g., Rp-cAMPS and CE3F4, respectively. To confirm the results with the CAMYEL assay, we used Swiss 3T3 cells and assessed the ability of cyclic nucleotide analogs to modulate the activity of Epac or PKA, determined by Rap1 activity or VASP phosphorylation, respectively. We used computational molecular modeling to analyze the interaction of analogs with Epac1. The results reveal a rapid means to identify modulators (potentially including allosteric inhibitors) of Epac activity that also provides insight into the mechanisms of Epac activation and inhibition.
    Journal of Biological Chemistry 02/2014; 289(12). DOI:10.1074/jbc.M114.548636 · 4.57 Impact Factor
  • Brian P Head · Hemal H Patel · Paul A Insel
    Biochimica et Biophysica Acta (BBA) - Biomembranes 02/2014; 1838:532-545. · 3.84 Impact Factor
  • Catherine M. Fuller · Paul A. Insel
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    ABSTRACT: No abstract.
    AJP Cell Physiology 01/2014; 306(C1-C2). DOI:10.1152/ajpcell.00342.2013 · 3.78 Impact Factor
  • David Lu · Paul A Insel
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    ABSTRACT: Tissue fibrosis occurs as a result of the dysregulation of extracellular matrix (ECM) synthesis. Tissue fibroblasts, resident cells responsible for the synthesis and turnover of ECM, are regulated via numerous hormonal and mechanical signals. The release of intracellular nucleotides and their resultant autocrine/paracrine signaling have been shown to play key roles in the homeostatic maintenance of tissue remodeling and in fibrotic response post-injury. Extracellular nucleotides signal through P2 nucleotide and P1 adenosine receptors to activate signaling networks that regulate the proliferation and activity of fibroblasts, which, in turn, influence tissue structure and pathologic remodeling. An important component in the signaling and functional responses of fibroblasts to extracellular ATP and adenosine is the expression and activity of ecto-nucleotideases that attenuate nucleotide-mediated signaling, and thereby integrate P2 receptor- and subsequent adenosine receptor-initiated responses. Results of studies of the mechanisms of cellular nucleotide release and the effects of this autocrine/paracrine signaling axis on fibroblast-to-myofibroblast conversion and the fibrotic phenotype have advanced understanding of tissue remodeling and fibrosis. This review summarizes recent findings related to purinergic signaling in the regulation of fibroblasts and the development of tissue fibrosis in the heart, lungs, liver and kidney.
    AJP Cell Physiology 12/2013; 306(9). DOI:10.1152/ajpcell.00381.2013 · 3.78 Impact Factor
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    ABSTRACT: Tissue fibrosis is characterized by excessive production, deposition and contraction of the extracellular matrix (ECM). The second messenger cyclic AMP (cAMP) has anti-fibrotic effects in fibroblasts from several tissues, including cardiac fibroblasts (CFs): Increased cellular cAMP levels can prevent the transformation of CFs into pro-fibrogenic myofibroblasts, a critical step that precedes increased ECM deposition and tissue fibrosis. Here we tested two hypotheses: 1) myofibroblasts have a decreased ability to accumulate cAMP in response to G protein-coupled receptor (GPCR) agonists and 2) increasing cAMP will not only prevent, but also reverse, the myofibroblast phenotype. We found that myofibroblasts produce less cAMP in response to GPCR agonists or forskolin and have decreased expression of several adenylyl cyclase (AC) isoforms and increased expression of multiple cyclic nucleotide phosphodiesterases (PDEs). Furthermore, we find that forskolin-promoted increases in cAMP or N6-Phe-cAMP, a PKA-selective analog, reverses the myofibroblast phenotype, as assessed by the expression of collagen Iα1, α-smooth muscle actin, plasminogen activator inhibitor-1 and cellular contractile abilities, all hallmarks of a fibrogenic state. These results indicate that: 1) altered expression of AC and PDE isoforms yield a decrease in cAMP concentrations of cardiac myofibroblasts (relative to CFs) that likely contribute to their pro-fibrotic state, and 2) approaches to increase cAMP concentrations not only prevent fibroblast-to-myofibroblast transformation but also can reverse the pro-fibrotic myofibroblastic phenotype. We conclude that therapeutic strategies designed to enhance cellular cAMP concentrations in CFs may provide a means to reverse excessive scar formation following injury and to treat cardiac fibrosis.
    Molecular pharmacology 10/2013; 84(6). DOI:10.1124/mol.113.087742 · 4.13 Impact Factor
  • Owen J T McCarty · Michael R King · Paul A Insel
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    ABSTRACT: Editorial.
    AJP Cell Physiology 09/2013; DOI:10.1152/ajpcell.00295.2013 · 3.78 Impact Factor
  • Brian P Head · Hemal H Patel · Paul A Insel
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    ABSTRACT: The plasma membrane in eukaryotic cells contains microdomains that are enriched in certain glycosphingolipids, gangliosides, and sterols (such as cholesterol) to form membrane/lipid rafts (MLR). These regions exist as caveolae, morphologically observable flask-like invaginations, or as a less easily detectable planar form. MLR are scaffolds for many molecular entities, including signaling receptors and ion channels that communicate extracellular stimuli to the intracellular milieu. Much evidence indicates that this organization and/or the clustering of MLR into more active signaling platforms depends upon interactions with and dynamic rearrangement of the cytoskeleton. Several cytoskeletal components and binding partners, as well as enzymes that regulate the cytoskeleton, localize to MLR and help regulate lateral diffusion of membrane proteins and lipids in response to extracellular events (e.g., receptor activation, shear stress, electrical conductance, and nutrient demand). MLR regulate cellular polarity, adherence to the extracellular matrix, signaling events (including ones that affect growth and migration), and are sites of cellular entry of certain pathogens, toxins and nanoparticles. The dynamic interaction between MLR and the underlying cytoskeleton thus regulates many facets of the function of eukaryotic cells and their adaptation to changing environments. Here, we review general features of MLR and caveolae and their role in several aspects of cellular function, including polarity of endothelial and epithelial cells, cell migration, mechanotransduction, lymphocyte activation, neuronal growth and signaling, and a variety of disease settings. This article is part of a Special Issue entitled: Reciprocal influences between cell cytoskeleton and membrane channels, receptors and transporters.
    Biochimica et Biophysica Acta 07/2013; DOI:10.1016/j.bbamem.2013.07.018 · 4.66 Impact Factor
  • Charles Goldberg · Paul A Insel
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    ABSTRACT: Many aspects of MD-PhD training are not optimally designed to prepare students for their future roles as translational clinician-scientists. The transition between PhD research efforts and clinical rotations is one hurdle that must be overcome. MD-PhD students have deficits in clinical skills compared with those of their MD-only colleagues at the time of this transition. Reimmersion programs (RPs) targeted to MD-PhD students have the potential to help them navigate this transition.The authors draw on their experience creating and implementing an RP that incorporates multiple types of activities (clinical exam review, objective structured clinical examination, and supervised practice in patient care settings) designed to enhance the participants' skills and readiness for clinical efforts. On the basis of this experience, they note that MD-PhD students' time away from the clinical environment negatively affects their clinical skills, causing them to feel underprepared for clinical rotations. The authors argue that participation in an RP can help students feel more comfortable speaking with and examining patients and decrease their anxiety regarding clinical encounters. The authors propose that RPs can have positive outcomes for improving the transition from PhD to clinical MD training in dual-degree programs. Identifying and addressing this and other transitions need to be considered to improve the educational experience of MD-PhD students.
    Academic medicine: journal of the Association of American Medical Colleges 06/2013; 88(6):745-747. DOI:10.1097/ACM.0b013e31828ffeeb · 2.93 Impact Factor
  • David Lu · Paul A Insel
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    ABSTRACT: The establishment of set points for cellular activities is essential in regulating homeostasis. Here we demonstrate key determinants of the fibrogenic set point of cardiac fibroblasts (CFs) by focusing on the pro-fibrotic activity of ATP, which is released by CFs. We tested the hypothesis that the hydrolysis of extracellular ATP by ectonucleoside triphosphate diphosphohydrolases (ENTPDs) regulates pro-fibrotic nucleotide signaling. We detected two ENTPD isoforms, ENTPD-1 and -2, in adult rat ventricular CFs. Partial knockdown of ENTPD-1 and -2 with siRNA increased basal extracellular ATP concentration and enhanced the pro-fibrotic effect of ATP stimulation. Sodium polyoxotungstate (POM)-1, an ENTPD inhibitor, not only enhanced the pro-fibrotic effects of exogenously added ATP but also increased basal expression of α-smooth muscle actin (α-SMA), plasminogen activator inhibitor (PAI)-1 and transforming growth factor (TGF)-β, collagen synthesis and gel contraction. Furthermore, we found that adenosine, a product of ATP hydrolysis by ENTPD, acts via A2B receptors to counterbalance the pro-fibrotic response to ATP. Removal of extracellular adenosine or inhibition of A2B receptors enhanced pro-fibrotic ATP signaling. Together, these results demonstrate the contribution of basally released ATP in establishing the set point for fibrotic activity in adult rat CFs and identify a key role for the modulation of this activity by hydrolysis of released ATP by ENTPDs. These findings also imply that cellular homeostasis and fibrotic response involves the integration of signaling that is pro-fibrotic by ATP and anti-fibrotic by adenosine and which is regulated by ENTPDs.
    Journal of Biological Chemistry 05/2013; 288(26). DOI:10.1074/jbc.M113.466102 · 4.57 Impact Factor

Publication Stats

15k Citations
2,805.10 Total Impact Points


  • 1980–2015
    • University of California, San Diego
      • • Department of Medicine
      • • Department of Pharmacology
      • • Department of Anesthesiology
      • • Department of Chemistry and Biochemistry
      • • Division of Cardiology
      San Diego, California, United States
    • University of California, Irvine
      Irvine, California, United States
  • 2013
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 2012
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2011
    • University of Wisconsin–Madison
      • Department of Medicine
      Madison, Wisconsin, United States
  • 2004
    • Naval Medical Center San Diego
      San Diego, California, United States
  • 2002
    • University of North Carolina at Chapel Hill
      • Department of Pharmacology
      North Carolina, United States
  • 1992–2002
    • University Hospital Essen
      Essen, North Rhine-Westphalia, Germany
  • 2001
    • Universitätsklinikum Halle (Saale)
      Halle-on-the-Saale, Saxony-Anhalt, Germany
  • 1995
    • Stanford University
      • Department of Pediatrics
      Palo Alto, California, United States
  • 1990
    • National University (California)
      San Diego, California, United States
  • 1988
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • University of California, Los Angeles
      • Division of Nephrology
      Los Ángeles, California, United States
  • 1987
    • National Institute of Mental Health (NIMH)
      베서스다, Maryland, United States
  • 1983
    • University of San Diego
      San Diego, California, United States
  • 1976–1980
    • University of California, San Francisco
      • • Department of Clinical Pharmacy
      • • Cardiovascular Research Institute
      • • Department of Biochemistry and Biophysics
      San Francisco, California, United States
  • 1977
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem, Israel