Selected Publications of Dr. Holz

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2019

2018

  •  A Vitamin B12 Conjugate of Exendin-4 Improves Glucose Tolerance Without Associated Nausea or Hypophagia in Rodents.

    Diabetes Obesity Metabolism, 2018

    This study reveals that the GLP-1 receptor agonist Exendin-4 can be conjugated to vitamin B12 so that its bioavailability favors a glucoregulatory effect at the pancreas rather than a C.N.S. mediated effect to induce nausea. This is an important finding because nausea is commonly observed in T2DM patients administered unconjugated Exendin-4. Evidently, B12 conjugation reduces the ability of Exendin-4 to penetrate the blood-brain barrier, thereby limiting its access to the C.N.S. This study originated as an inter-institutional collaboration of Dr. Holz with the laboratories of Drs. Robert P. Doyle (Syracuse University), Christian L. Roth (University of Washington) and Matthew R. Hayes (University of Pennsylvania).

  • Chimeric Peptide EP45 as a Dual Agonist at GLP-1 and NPY2R Receptors.

    Scientific Reports, 2018

    Reported here are “dual agonist” GPCR-activating properties of the chimeric peptide EP45 that incorporates amino acid motifs found within the blood glucose-lowering agent GLP-1 and the appetite-suppressing agent Peptide YY. Such dual-agonist properties of EP45 were validated in a new FRET assay developed at the Holz laboratory by Dr. Oleg G. Chepurny working in collaboration with Dr. Robert P. Doyle of the Syracuse University Chemistry Department. EP45 was designed by Dr. Doyle working with Syracuse University graduate student Ron L. Bonaccorso. Chimeric peptides such as EP45 are predicted to be of use for simultaneous treatment of diabetes and obesity.

  • a7 Nicotinic Acetylcholine Receptor Regulates the Function and Viability of L Cells

    Endocrinology, 2018

    This study was a collaboration with the laboratory of Dr. Robert N. Cooney of the Department of Surgery at SUNY Upstate in which the Holz laboratory participated in the discovery that the a7 nicotinic acetylcholine receptor is a pentameric cation channel that mediates stimulatory effects of GTS-21 on enteroendocrine L-cell GLP-1 release.

  • Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets.

    Diabetes, 2018

    Reported here are collaborative studies of the Holz and Thurmond labs working with Dr. Frank Schwede of the BIOLOG Life Sciences Institute to establish that in human islets from T2DM donors, the Epac selective cAMP analog 8-pCPT-2’-O-Me-cAMP-AM enables F-acting cytoskeletal remodeling so that insulin secretion is restored.

2017

        research/laboratory-research/Holz_SGP_Poster_20171.pptx

2016

  • Modeling Analysis of Inositol 1,4,5-Trisphosphate Receptor-Mediated Ca2+ Mobilization Under The Control Of Glucagon-Like Peptide-1 In Mouse Pancreatic Beta-Cells.
    Amer. J. Physiol. Cell Physiol. 2016
    This mathematical modeling paper concerns a collaboration of the Holz laboratory with Japanese investigators Yukari Takeda, Takao Shimayoshi, and Akinori Noma. The mathematical simulation studies provide insight concerning the findings originally reported by Kang, Holz, and co-workers in their 2005 paper published in the Journal of Physiology (A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic beta cells) when the Holz laboratory was based at New York University School of Medicine.

  • GPR119 Agonist AS1269574 Activates TRPA1 Cation Channels To Stimulate GLP-1 Secretion.
    Molecular Endocrinology,2016
    In studies of enteroendocrine cell lines, we find that the GPR119 agonist AS1269574 stimulates GLP-1 secretion in a surprisingly TRPA1 cation channel-mediated manner. However, AS1269574 also acts via GPR119 to stimulate proglucagon gene expression. Therefore, AS1269574 possesses unique “dual agonist” properties so that it promotes both GLP-1 release and GLP-1 biosynthesis.

  • Solution Structure and Constrained Molecular Dynamics Study of Vitamin B12 Conjugates of the Anorectic Peptide PYY(3-36).
    ChemMedChem, 2016
    This paper provides detailed structural and functional information concerning a Vitamin B12 conjugate of PYY(3-36) that was synthesized in the laboratory of Prof. Robert P. Doyle at the Syracuse University Department of Chemistry. The paper completes the thesis project of Syracuse University graduate Kelly E. Henry who spent time working in the Holz lab to validate this peptide's receptor activating properties.

  • PI3 Kinases p110alpha And PI3K-C2beta Negatively Regulate cAMP Via PDE3/8 To Control Insulin Secretion In Mouse And Human Islets.

    Molecular Metabolism, 2016

    This paper highlights our use of the new cAMP antagonist Rp-8-Br-cAMPS-pAB to demonstrate that cAMP-dependent insulin secretion is under the inhibitory control of phosphatidylinositol 3-kinase in pancreatic beta cells. The project was a collaboration with the laboratory of Dr. Patrick E. MacDonald of the University of Alberta, Canada.

  • Synthetic Small Molecule GLP-1 Secretagogues Prepared By Means Of A Three-Component Indole Annulation Strategy.

    Scientific Reports, 2016

    In a collaboration with Dr. Jimmy Wu of the Dartmouth College Chemistry Department, we identified the cycloalka[b]indole JWU-A021 to be a potent GLP-1 secretagogue with TRPA1 cation channel activating properties in the intestinal L-cells. The chemistry underlying the synthesis of JWU-A021 provides a new approach to combinatorial small molecule library construction for drug discovery efforts.

  • George G Holz Model of Beta-Cell Stimulus-Secretion Coupling Version 2

    Research Gate, 2016

    Illustrated is Version 2 of the Holz laboratory model of pancreatic beta-cell stimulus-secretion coupling. Incorporated into Version 2 are two new features: 1) the role of soluble adenylyl cyclase (sAC) as a mediator of glucose metabolism-stimulated cAMP production, and 2) the role of cAMP as a stimulus for Cdc42-Pak1 activation and cortical F-actin remodeling with consequent mobilization of a reserve pool (RP) of secretory granules to the plasma membrane for insulin exocytosis. Additional abbreviations: RRP, readily-releasable pool; GK, glucokinase; CA, carbonic anhydrase; GLP-1, glucagon-like peptide-1; G pro., G protein; tmAC, transmembrane adenylyl cyclase; Epac2, type 2 isoform of the guanine nucleotide exchange factor directly activated by cAMP; PKA, cAMP-dependent protein kinase; PDE, cyclic nucleotide phosphodiesterase; K-ATP, ATP-sensitive potassium channel; VDCC, voltage-dependent calcium channel; NSCC, non-selective cation channel; Kv, voltage-activated potassium channel; Kca; calcium-activated potassium channel; SERCA, sarcoendoplasmic reticulum calcium transporter; IP3R, inositol trisphosphate receptor; RYR, ryanodine receptor.

     All rights reserved:

     https://www.researchgate.net/publication/309726457_GGHolz_Beta_Cell_GSIS_Version2

     DOI:10.13140/RG.2.2.35500.46724 11/2016, DOI: 10.13140/RG.2.2.35500.46724

  • George G Holz High Throughput FRET Assays for Detection of cAMP

    Research Gate, 2016

    Illustrated is Version 2 for Holz Lab Protocols concerning high throughput FRET-based detection of cAMP in a 96-well format. The assay uses the 4th generation Epac1 biosensor H188 invented by the Jalink lab (Klarenbeek 2015; PLOS One). HEK293 cell clones stably expressing this biosensor were created in the Holz lab by Dr. Oleg G. Chepurny. The assay takes advantage of cAMP analogs provided by Dr. Frank Schwede of the Biolog Life Science Institute. Specific details of the assay are to be found in: Holz GG, Leech CA, Roe MW, Chepurny OG. High-throughput FRET assays for fast time-dependent detection of cyclic AMP in pancreatic beta cells. "Cyclic Nucleotide Signaling". Xiaodong Cheng, ed. Taylor and Francis Group. CRC Press, 2015; 35-60.

     All rights reserved:

     https://www.researchgate.net/publication/310240169_GGHolz_High_Throughput_FRET_cAMP_Version2

     DOI: 10.13140/RG.2.2.35097.42088 11/2016,

     DOI: 10.13140/RG.2.2.35097.42088

2015

  • Molecular Basis of cAMP Signaling in Pancreatic Beta Cells
    Chapter 25, Islets of Langerhans, 2nd Edition, 2015
    This review commissioned by Springer is Chapter 25 of the Second Edition of the Islets of Langerhans with Md. Shahidul Islam of the Karolinska Institute serving as Editor.

  • Vitamin B12 Conjugation of Peptide-YY(3-36) Decreases Food Intake Compared to Native Peptide-YY(3-36) Upon Subcutaneous Administration in Male Rats
    Endocrinology, 2015
    This paper concerns a collaboration of the Holz laboratory with Dr. Robert P. Doyle of Syracuse University's Department of Chemistry and it is the first to demonstrate that increased bioavailability of a subcutaneously administered peptide can be achieved through the use of Vitamin B12 conjugation chemistry. The published findings are the basis of a PhD thesis project of Syracuse University graduate student Kelly E. Henry.

  • High-Throughput FRET Assays for Fast Time-Dependent Detection of cAMP in Pancreatic Beta Cells
    Chapter 3, Cyclic Nucleotide Signaling, 2015
    This review describes the details of a novel FRET-based assay for use in the detection of cAMP that was developed starting in 2009 (Chepurny et al.  JBC, 2009) in the Holz laboratory for use in studies of GPCR activation.

  • Rp-cAMPS Prodrugs Reveal the cAMP-Dependence of First-Phase Glucose-Stimulated Insulin Secretion
  • Molecular Endocrinology, 2015
  • This research paper describes the synthesis and characterization of highly membrane permeable cAMP analogs that are bioactivatable prodrugs and that act as potent antagonists of PKA and Epac signaling in living cells. In studies of human and rat islets of Langerhans, one such antagonist (Rp-8-Br-cAMPS-pAB) is shown to be a selective inhibitor of first-phase glucose-stimulated insulin secretion. This finding resolves a 40-year debate concerning whether or not cAMP signaling is essential in order for glucose alone to stimulate insulin secretion.

  • Enhanced Peptide Stability Against Protease Digestion Induced by Intrinsic Factor Binding of a Vitamin B12 Conjugate of Exendin-4.
  • Molecular Pharmaceutics, 2015
  • Intrinsic factor (IF) is secreted by parietal cells of the stomach, and it mediates intestinal absorption of dietary Vitamin B12. Potentially, a B12-Exendin-4 conjugate would be an orally administrable GLP-1 receptor agonist by virtue of its ability to bind IF so that intestinal absorption would be facilitated. However, proteolytic digestion of Exendin-4 within the intestine might lead to inactivation of the conjugate. This paper revealed that binding of B12-Exendin-4 to IF conferred a protective effect against protease digestion. The published findings are the basis of a PhD thesis project of Syracuse University graduate student Ron L. Bonaccorso.

2014

  • New Insights Concerning the Molecular Basis for Defective Glucoregulation in Soluble Adenylyl Cyclase Knockout Mice
    Biochimica et Biophysica Acta Molecular Basis of Disease 2014
    This review is one chapter of a Special Issue of BBA organized by Drs. Lonny Levin and Jochen Buck of Cornell University serving as guest Editors.

  • Regulation of glucose homeostasis by GLP-1
    Progress in Molecular Biology and Translational Science 2014
    This review summarizes the current state of knowledge regarding how GLP-1 influences systemic glucose homeostasis in humans with type 2 diabetes and in various animal models of type 2 diabetes. Also provided is an update concerning GLP-1 based drug development strategies that target the GLP-1 receptor or DPP-IV in order to lower levels of blood glucose.

2013

  • Identification and characterization of small molecules as potent and specific EPAC2 antagonists.
    Journal of Medicinal Chemistry 2013
    This paper describes the synthesis and properties of novel small molecule Epac2 antagonists including HJC0350. The specificity of these antagonists was evaluated by the Holz lab in FRET-based assays of Epac2 activation. The work was a collaboration of the Holz laboratory with Drs. Chen, Tsalkova, Mei, Cheng, and Zhou of the University of Texas Medical Branch in Galveston, TX.

  • Synthesis, characterization and pharmacodynamics of vitamin-B12-conjugated glucagon-like peptide-1.
    Chem Med Chem 2013
    Vitamin B12 conjugates of GLP-1 are under investigation as orally administrable blood glucose-lowering agents. These conjugates bind to gastric instrinsic factor and undergo intestinal absorption using the body's own B12 uptake mechanism. For this study, the Holz laboratory collaborated with Dr. Robert P. Doyle of the Syracuse University Department of Chemistry in a thesis project of SU graduate student Susan Clardy-James.

  • Epac2 makes a new impact in beta-cell biology.
    Diabetes 2013
    This invited Commentary summarizes findings demonstrating that under conditions of insulin resistance induced by a high fat diet, the global knockout of Epac2 gene expression leads to beta-cell decompensation that is measurable as defective glucose-stimulated insulin secretion in mice. The Commentary concerns findings published by the laboratory of Dr. Mehboob A. Hussain at Johns Hopkins University School of Medicine (Song et al., Diabetes, 2013).

  • Stimulation of proglucagon gene expression by human GPR119 in enteroendocrine L-cell line GLUTag.
    Molecular Endocrinology 2013
    The Holz laboratory collaborated with the laboratories of Dr. Friedrich W. Herberg (Kassel, Germany) and Xiaodong Cheng (Galveston, TX) in order to demonstrate that the fatty acid amide receptor GPR119 stimulates proglucagon gene expression, a necessary first step in GLP-1 biosynthesis. In this study, a new 6-Bn-cAMP-AM analog developed by the BIOLOG Life Sci. Inst. (Bremen, Germany) was also demonstrated to be a selective activator of proglucagon gene expression under the control of RII alpha/beta regulatory subunits of PKA.

  • Carbon dioxide/bicarbonate and calcium-regulated soluble adenylyl cyclase as a physiological ATP sensor.
    Journal of Biological Chemistry 2013
    Soluble adenylyl cyclase (sAC) expressed in pancreatic beta cells can generate cAMP in response to an elevation of blood glucose concentration. The glucose-dependence of sAC activity is explained by its coordinate activation in response to glucose-derived metabolic coupling factors (bicarbonate ion, calcium, ATP). We also find that sAC is an intermediary linking beta-cell glucose metabolism to islet insulin secretion. This paper constituted a collaboration of the Holz laboratory with the laboratories of Drs. Lonny Levin, Jochen Buck, and Geoffrey W.G. Sharp of Cornell University.

  • Leptin-stimulated K-ATP channel trafficking: a new paradigm for beta-cell stimulus-secretion coupling?
    Islets 2013
    Park et al. (PNAS 2013) find that leptin stimulates AMPK in order to promote K-ATP channel trafficking from cytosolic vesicles to the plasma membrane of beta cells. Such findings provide an unexpected explanation for the earlier report of Kieffer et al. (Diabetes 1997) demonstrating increased K-ATP channel current and reduced insulin secretion in response to leptin. Conceivably, K-ATP channel trafficking can operate in a reverse mode in order to promote depolarization-induced insulin secretion. For example, high concentrations of glucose may suppress AMPK activity, thereby reducing K-ATP channel density and current in the plasma membrane.

2012

  • Role of phospholipase C-epsilon in physiological phosphoinositide signaling networks, Cellular Signaling 2012
    This review concerning PLC-epsilon was a collaboration of Drs. Alan V. Smrcka, Joan Heller Brown, and George G. Holz. Summarized are current concepts regarding how Epac signals through Rap in order to control PLC-epsilon activity, thereby influencing Ca2+ handling, excitation-contraction coupling, and exocytosis in various cell types.

  • cAMP Sensor Epac and Gastrointestinal Function, Physiology of the Gastrointestinal Tract, Fifth Edition 2012
    Summarized in this handbook chapter are the surprisingly diverse roles Epac proteins play in gastrointestinal function. The work was a collaboration of the Holz laboratory with Dr. Xiaodong Cheng of the University of Texas Medical Branch in Galveston, TX.

  • Isoform-specific antagonists of exchange proteins directly activated by cAMP, Proceedings of the National Academy of Sciences 2012
    A major breakthrough for the field of signal transduction research was the discovery by Dr. Xiaodong Cheng of small molecule compounds (ESI-05, ESI-07) that specifically inhibit Epac2 while leaving Epac1 and PKA unaffected. The specificity of ESI-05 and ESI-07 was validated in FRET-based assays of Epac or PKA activation, as performed in the Holz laboratory by Drs. Oleg G. Chepurny and Colin A. Leech.

2011

  • Phospholipase C-epsilon links Epac2 activation to the potentiation of glucose-stimulated insulin secretion from mouse islets of Langerhans, Islets 2011
    This report provided the first evidence that a novel Epac2 and Rap1 -regulated PLC-epsilon mediates the action of cAMP to potentiate glucose-stimulated insulin secretion from mouse islets. Consistent with this concept, the insulin secretagogue action of an Epac activator (8-pCPT-2'-O-Me-cAMP-AM) was found to be diminished in islets of Epac2 and PLC-epsilon KO mice. The study was a collaboration of the Holz laboratory with Dr. Youming Lu who provided the Epac2 KO mice, and Dr. Alan V. Smrcka who provided the PLC-epsilon KO mice.

  • Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic beta cells, Progress in Biophysics and Molecular Biology 2011
    This review provided an update concerning the molecular basis for incretin hormone action, as it pertains to insulin secretion under the control of GLP-1. New findings reported in this review included the discovery of Dr. Igor Dzhura that an Epac activator (8-pCPT-2 '-O-Me-cAMP-AM) initiated electrical "bursting" activity in mouse islets. This bursting activity was comprised of action potentials, and it occurred in synchrony with oscillations of cytosolic [Ca2+] that are known to "trigger" pulsatile insulin secretion.

2010

2009

2008

2007

2006

  • Cell physiology of cAMP sensor Epac, The Journal of Physiology Topical Review 2006
    This Topical review highlights the emerging role of cAMP sensor Epac as a central player in multiple aspects of cell physiology. The novel pharmacological properties and physiological actions of Epac-selective cAMP analogs (ESCAs) are also updated.

  • Simultaneous Optical Measurements of Cytosolic Ca2+ and cAMP in Single Cells, Science's STKE 2006
    Our collaboration with the laboratory of Dr. Michael W. Roe at the University of Chicago has generated this ground-breaking technology that allows for the very first time, the simultaneous digital imaging of cAMP and calcium concentrations in single living cells. The detailed protocols described here are an extension of the prior study of the Roe, Lohse, and Holz labs (Landa et al. 2005, see below).

  • cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic ß cells and rat INS-1 cells, Journal of Physiology 2006
    This research paper describes a novel form of ion channel modulation in which the activity of pancreatic beta cell ATP-sensitive potassium channels is shown to be be inhibited by Epac-selective cAMP analogs. The significance of this finding is that it establishes Epac, a cAMP-regulated guanine nucleotide exchange factor (cAMP-GEF), to be a likely target for pharmacological intervention in the treatment of type 2 diabetes mellitus.

2005

  • Diabetes Outfoxed by GLP-1?, Science's STKE 2005
    This perspective published originally at Science magazine's STKE web site provides our view of how GLP-1 influences pancreatic beta cell growth and differentiation.

  • A cAMP and Ca2+ coincidence detector in support of Ca2+-induced Ca2+ release in mouse pancreatic ß cells, Journal of Physiology 2005
    This research paper is the first to establish the phenomenon of Second Messenger Coincidence Detection as a key cellular signaling event underlying the ability of a GLP-1 receptor agonist (Exendin-4, also known as Byetta) to stimulate pancreatic beta cell function.

  • Interplay of Ca2+ and cAMP Signaling in the Insulin-secreting MIN6 ß-Cell Line, Journal of Biological Chemistry 2005
    This research paper is the first to demonstrate that a newly-developed Epac-based FRET reporter can be activated as a consequence of GLP-1 receptor stimulation in pancreatic beta cells. The significance of this finding is that it establishes the cAMP-binding domain of Epac to be sensitive to the increase of cytosolic cAMP concentration that results upon stimulation of beta cells with Exendin-4. This report is an outgrowth of collaborative studies with the laboratory of Dr. Michael Roe of the University of Chicago.

2004

2003

2002

2001

2000

1990-1999

1986-1989

  • G Proteins Couple a-Adrenergic and GABAb Receptors to Inhibition of Peptide Secretion from Peripheral Sensory Neurons, Journal of Neuroscience 1989
    This research report is the culmination of postdoctoral studies performed by Dr. Holz while working in the laboratory of Dr. Kathleen Dunlap at Tufts University School of Medicine. The findings demonstrate that alpha-adrenergic receptors, GABA-B receptors, Pertussis Toxin-Sensitive G proteins, and Voltage-Dependent Calcium Channels constitute a "signaling module" which when activated, generates presynaptic inhibition of neuropeptide secretion from peripheral sensory neurons.

  • Characterization of the Electrically Evoked Release of Substance P from Dorsal Root Ganglion Neurons: Methods and Dihydropyridine Sensitivity, Journal of Neuroscience 1988
    The role of L-type and N-type Voltage-Dependent Calcium Channels as determinants of neuropeptide secretion was first established in this study examining the exocytosis of Substance P from peripheral sensory neurons. This is the first study to demonstrate that the electrically-evoked release of a neuropeptide results from depolarization-induced activation of omega-conotoxin GVIA-sensitive N-type Calcium channels.

  • G proteins as regulators of ion channel function, Trends In Neuroscience 1987
    This review provided the impetus for numerous studies examining the role of heterotrimeric G proteins as signaling intermediaries linking G protein-coupled receptors to the modulation of Calcium and Potassium channels in excitable cells.

  • Modifying channel function, Nature 1986 News and Views
    This is the News and Views article which accompanied our 1986 report in Nature concering G protein regulation of voltage-dependent calcium channels.

  • GTP-binding proteins mediate transmitter inhibition of voltage-dependent calcium channels, Nature 1986
    This is the paper that established a link between activation of G proteins and the inhibition of voltage-dependent calcium channels. It was the most highly cited paper in the field of Neuroscience for the year 1986 according to the ISI. Publication of this study was facilitated by the generosity of Dr. Ronald D. Sekura of the NIH who provided Dr. Holz purified preparations of Bordetella pertussis toxin, which at that time were not commercially available.

  • Serotonin Decreases the Duration of Action Potentials Recorded from Tetraethylammonium-Treated Bullfrog Dorsal Root Ganglion Cells, Journal of Neuroscience 1986
    This research report summarizes the Ph.D. studies of Dr. Holz performed while working in the laboratory of Dr. Edmund G. Anderson, Chairman of Pharmacology at the University of Illinois in Chicago. The role of serotonin receptors in the generation of presynaptic inhibition was investigated in electrophysiological studies of primary sensory neurons.

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