ArticleMolecular endocrinology (Baltimore, Md.)2015
Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion.
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Article in Molecular endocrinology (Baltimore, Md.), 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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24citing papers in PubMed
4.1field-weighted citation impact, top 6% of its field
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 38 citations in OpenAlex.
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- Sulfur and Selenium Modifications at Phosphorus Atom in Nucleoside Monophosphates, Activity and Potential Applications.Current medicinal chemistry · 2026Review
- A Novel Steroidogenic Action of Anti-Müllerian Hormone in Teleosts: Evidence from the European Sea Bass Male (International journal of molecular sciences · 2025Article
- Noncanonical Regulation of cAMP-Dependent Insulin Secretion and Its Implications in Type 2 Diabetes.Comprehensive Physiology · 2023Article
- The Critical Biomarkers Identification of Insulin Signaling Involved in Initiating cAMP Signaling Mediated Salivary Secretion in Sjogren Syndrome: Transcriptome Sequencing in NOD Mice Model.Biological procedures online · 2022Article
- Clinical relevance of dual agonist of glucagon and glucagon-like peptide-1 receptors to achieve functional restoration of first- and second-phase insulin secretion.Journal of diabetes investigation · 2022Article
- Intra-islet glucagon confers β-cell glucose competence for first-phase insulin secretion and favors GLP-1R stimulation by exogenous glucagon.The Journal of biological chemistry · 2022Article
- Cyclic Nucleotide (cNMP) Analogues: Past, Present and Future.International journal of molecular sciences · 2021Review
- Depolarization induces nociceptor sensitization by CaV1.2-mediated PKA-II activation.The Journal of cell biology · 2021Article
- GPharmacological reviews · 2021Review
- Cyclic AMP-dependent activation of ERK via GLP-1 receptor signalling requires the neuroendocrine cell-specific guanine nucleotide exchanger NCS-RapGEF2.Journal of neuroendocrinology · 2021Article
- Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis.Journal of medicinal chemistry · 2021Article
- Glucose stimulates somatostatin secretion in pancreatic δ-cells by cAMP-dependent intracellular CaThe Journal of general physiology · 2019Article
- Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP.The Journal of biological chemistry · 2019Article
- β Cell tone is defined by proglucagon peptides through cAMP signaling.JCI insight · 2019Article
- GLP-1 signaling suppresses menin's transcriptional block by phosphorylation in β cells.The Journal of cell biology · 2019Article
- Article
- PKA-RII subunit phosphorylation precedes activation by cAMP and regulates activity termination.The Journal of cell biology · 2018Article
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- Chimeric peptide EP45 as a dual agonist at GLP-1 and NPY2R receptors.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
14 authors at 7 institutions in 3 countries.
Frank SchwedeBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Oleg G ChepurnyBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Melanie KaufholzBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Daniela BertinettiBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Colin A LeechBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Over CabreraBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Yingmin ZhuBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Fang MeiBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Xiaodong ChengBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Jocelyn E Manning FoxBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Patrick E MacDonaldBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Hans-G GenieserBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
Friedrich W HerbergBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
George G HolzBIOLOG Life Science Institute (F.S., H.-G.G.), 28199 Bremen, Germany; Departments of Medicine (O.G.C., C.A.L., G.G.H.) and Pharmacology (G.G.H.), State University of New York, Upstate Medical University, Syracuse, New York 13210; Department of Biochemistry (M.K., D.B., F.W.H.), University of Kassel, 34132 Kassel, Germany; Eli Lilly and Company (O.C.), Indianapolis, Indiana 46225; Department of Integrative Biology and Pharmacology (Y.Z., F.M., X.C.), Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center, Houston, Texas 77030; Department of Pharmacology and the Alberta Diabetes Institute (J.E.M.F., P.E.M.), University of Alberta, Edmonton, Canada AB T6G 2E1.
SUNY Upstate Medical University · USUniversity of Kassel · DEBiolog Life Science Institute · DEThe University of Texas Health Science Center at Houston · USUniversity of Alberta · CABrown Foundation · USEli Lilly (United States) · US
Funding
Epac/cAMP-GEF, A Novel Intracellular cAMP ReceptorR01GM066170 · NIGMS · UNIVERSITY OF TEXAS MEDICAL BR GALVESTON · PI CHENG, XIAODONG · 2003 to 2017
$4.6MMolecular Basis of Antidiabetogenic Hormone ActionR01DK069575 · NIDDK · UPSTATE MEDICAL UNIVERSITY · PI HOLZ, GEORGE G · 2007 to 2017
$2.9MNIDDK NIH HHS R01 DK069575NIDDK NIH HHS R01-DK069575NIGMS NIH HHS R01 GM066170NIGMS NIH HHS R01-GM066170
Abstract
cAMP-elevating agents such as the incretin hormone glucagon-like peptide-1 potentiate glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells. However, a debate has existed since the 1970s concerning whether or not cAMP signaling is essential for glucose alone to stimulate insulin secretion. Here, we report that the first-phase kinetic component of GSIS is cAMP-dependent, as revealed through the use of a novel highly membrane permeable para-acetoxybenzyl (pAB) ester prodrug that is a bioactivatable derivative of the cAMP antagonist adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS). In dynamic perifusion assays of human or rat islets, a step-wise increase of glucose concentration leads to biphasic insulin secretion, and under these conditions, 8-bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer, 4-acetoxybenzyl ester (Rp-8-Br-cAMPS-pAB) inhibits first-phase GSIS by up to 80%. Surprisingly, second-phase GSIS is inhibited to a much smaller extent (≤20%). Using luciferase, fluorescence resonance energy transfer, and bioluminescence resonance energy transfer assays performed in living cells, we validate that Rp-8-Br-cAMPS-pAB does in fact block cAMP-dependent protein kinase activation. Novel effects of Rp-8-Br-cAMPS-pAB to block the activation of cAMP-regulated guanine nucleotide exchange factors (Epac1, Epac2) are also validated using genetically encoded Epac biosensors, and are independently confirmed in an in vitro Rap1 activation assay using Rp-cAMPS and Rp-8-Br-cAMPS. Thus, in addition to revealing the cAMP dependence of first-phase GSIS from human and rat islets, these findings establish a pAB-based chemistry for the synthesis of highly membrane permeable prodrug derivatives of Rp-cAMPS that act with micromolar or even nanomolar potency to inhibit cAMP signaling in living cells.
Indexed as
8-Bromo Cyclic Adenosine MonophosphateAnimalsBenzyl AlcoholCell LineCyclic AMPCyclic AMP-Dependent Protein KinasesCytosolEnzyme ActivationEsterasesFemaleFluorescence Resonance Energy TransferGene Expression RegulationGlucoseGuanine Nucleotide Exchange FactorsHoloenzymesHumans8-bromoadenosine-3',5'-cyclic monophosphorothioate8-Bromo Cyclic Adenosine MonophosphateBenzyl AlcoholCre recombinaseCyclic AMPCyclic AMP-Dependent Protein KinasesEsterasesGlucoseGuanine Nucleotide Exchange FactorsHoloenzymesInsulinIntegrasesLuciferasesProdrugsRAPGEF3 protein, humanRAPGEF4 protein, humanThionucleotides
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.