Selected Publications of Dr. Holz

All downloadable files are in PDF format.


  • 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.


  • 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.


  • Role of phospholipase C-epsilon in physiological phosphoinositide signaling networks, Cellular Signalling 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.


  • 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.






  • 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 β 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.


  • 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 β 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 β-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.








  • G Proteins Couple α-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.