Ong Moua

University of Colorado Anschutz Medical Campus

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Kurt G. Beam

University of Colorado Denver

Roger A. Bannister

National Institute on Aging

John C. Hutton

University of Colorado Health

Howard W. Davidson

University of Colorado Denver

George S. Eisenbarth

University of Colorado Health

Janet M. Wenzlau

University of Colorado Denver

Joshua D. Ohrtman

University of Colorado Denver

Suparna A. Sarkar

New York University

Liping Yu

University of Colorado Anschutz Medical Campus

Alexander Polster

University of Colorado Denver

Cooperative Institutions

University of Colorado Denver

University of Colorado Anschutz Medical Campus

University of Colorado Health

The Medical Center of Aurora

University of Colorado Boulder

Diabetes Australia

University of Colorado System

University of California, Davis

University of Cologne

Centro Universitario de Araras Dr Edmunso Ulson

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Induction of Indoleamine 2,3-Dioxygenase by Interferon-γ in Human Islets

Diabetes (2006)

Suparna A. Sarkar Randall Wong Seija I. Hackl Ong Moua Ronald G. Gill

Indoleamine 2,3-dioxygenase (IDO) catalyzes the initial, rate-limiting step of tryptophan (Trp) catabolism along the kynurenine (KYN) pathway, and its induction in cells of the immune system in response to cytokines has been implicated in the regulation of antigen presentation and responses to cell-mediated immune attack. Microarray and quantitative PCR analyses of isolated human islets incubated with interferon (IFN)-gamma for 24 h revealed increased expression of IDO mRNA (>139-fold) and Trp-tRNA synthase (WARS) (>17-fold) along with 975 other transcripts more than threefold, notably the downstream effectors janus kinase (JAK)2, signal transducer and activator of transcription (STAT)1, IFN-gamma regulatory factor-1, and several chemokines (CXCL9/MIG, CXCL10/IP10, CXCL11/1-TAC, CCL2, and CCL5/RANTES) and their receptors. IDO protein expression was upregulated in IFN-gamma-treated islets and accompanied by increased intracellular IDO enzyme activity and the release of KYN into the media. The response to IFN-gamma was countered by interleukin-4 and 1alpha-methyl Trp. Immunohistochemical localization showed IDO to be induced in cells of both endocrine, including pancreatic duodenal homeobox 1-positive beta-cells, and nonendocrine origin. We postulate that in the short term, IDO activation may protect islets from cytotoxic damage, although chronic exposure to various Trp metabolites could equally lead to beta-cell attrition.

Indoleamine 2,3-dioxygenase

CCL5

10.2337/db06-0617

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Citations (90)

Effects of Alanine Substitutions for Highly-Conserved Phenylalanines in the Skeletal Muscle L-Type Calcium Channel

Biophysical Journal (2010)

Roger A. Bannister Ong Moua Joshua D. Ohrtman Christopher A. Ahern Kurt G. Beam

Homomeric

Alanine

Wild type

10.1016/j.bpj.2009.12.2810

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Citations (1)

Effects of Substituting Tryptophan for Basic Residues in the S4 Voltage-Sensing Helices of CaV1.1

Biophysical Journal (2013)

Roger A. Bannister Ong Moua Kurt G. Beam

Wild type

Cav1.2

10.1016/j.bpj.2012.11.1633

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How heterogeneity in glucokinase and gap junction coupling determines the islet electrical response

bioRxiv (Cold Spring Harbor Laboratory) (2019)

JaeAnn M. Dwulet Nasir Ludin Robert A. Piscopio Wolfgang E. Schleicher Ong Moua

ABSTRACT Understanding how cell sub-populations in a tissue impact the function of the overall system is often challenging. There is extensive heterogeneity among insulin-secreting β-cells within islets of Langerhans, including their insulin secretory response and gene expression profile; and this heterogeneity can be altered in diabetes. Several studies have identified variations in nutrient sensing between β-cells, including glucokinase (GK) levels, mitochondrial function or expression of genes important for glucose metabolism. Sub-populations of β-cells with defined electrical properties can disproportionately influence islet-wide free-calcium activity ([Ca 2+ ]) and insulin secretion, via gap junction electrical coupling. However, it is poorly understood how sub-populations of β-cells with altered glucose metabolism may impact islet function. To address this, we utilized a multicellular computational model of the islet in which a population of cells deficient in GK activity and glucose metabolism was imposed on the islet, or where β-cells were heterogeneous in glucose metabolism and GK kinetics were altered. This included simulating Glucokinase gene ( GCK ) mutations that cause monogenic diabetes. We combined these approaches with experimental models in which gck was genetically deleted in a population of cells or GK was pharmacologically inhibited. In each case we modulated gap junction electrical coupling. Both the simulated islet and the experimental system required 30-50% of the cells to have near-normal glucose metabolism. Below this number, the islet lacked any glucose-stimulated [Ca 2+ ] elevations. In the absence of electrical coupling the change in [Ca 2+ ] was more gradual. As such, given heterogeneity in glucose metabolism, electrical coupling allows a large minority of cells with normal glucose metabolism to promote glucose-stimulated [Ca 2+ ]. If insufficient numbers of cells are present, which we predict can be caused by a subset of GCK mutations that cause monogenic diabetes, electrical coupling exacerbates [Ca 2+ ] suppression. This demonstrates precisely how heterogeneous β-cell populations interact to impact islet function. SIGNIFICANCE Biological tissues contain heterogeneous populations of cells. Insulin-secreting β-cells within the islets of Langerhans are critical for regulating blood glucose homeostasis. β-cells are heterogeneous but it is unclear how the islet response is impacted by different cell populations and their interactions. We use a multicellular computational model and experimental systems to predict and quantify how cellular populations defined by varied glucose metabolism interact via electrical communication to impact islet function. When glucose metabolism is heterogeneous, electrical coupling is critical to promote electrical activity. However, when cells deficient in glucose metabolism are in the majority, electrical activity is completely suppressed. Thus modulating electrical communication can promotes islet electrical activity, following dysfunction caused by gene mutations that impact glucose metabolism.

Glucokinase

Carbohydrate Metabolism

10.1101/696096

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Citations (1)

Effects of Tryptophan Substitutions for Highly-Conserved Phenylalanines in the Skeletal Muscle L-Type Calcium Channel

Biophysical Journal (2012)

Roger A. Bannister Ong Moua Christopher A. Ahern Kurt G. Beam

Shaker

10.1016/j.bpj.2011.11.2365

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Apparent lack of physical or functional interaction between CaV1.1 and its distal C terminus

The Journal of General Physiology (2015)

Joshua D. Ohrtman Christin F. Romberg Ong Moua Roger A. Bannister S. Rock Levinson

CaV1.1 acts as both the voltage sensor that triggers excitation–contraction coupling in skeletal muscle and as an L-type Ca2+ channel. It has been proposed that, after its posttranslational cleavage, the distal C terminus of CaV1.1 remains noncovalently associated with proximal CaV1.1, and that tethering of protein kinase A to the distal C terminus is required for depolarization-induced potentiation of L-type Ca2+ current in skeletal muscle. Here, we report that association of the distal C terminus with proximal CaV1.1 cannot be detected by either immunoprecipitation of mouse skeletal muscle or by colocalized fluorescence after expression in adult skeletal muscle fibers of a CaV1.1 construct labeled with yellow fluorescent protein (YFP) and cyan fluorescent protein on the N and C termini, respectively. We found that L-type Ca2+ channel activity was similar after expression of constructs that either did (YFP-CaV1.11860) or did not (YFP-CaV1.11666) contain coding sequence for the distal C-terminal domain in dysgenic myotubes null for endogenous CaV1.1. Furthermore, in response to strong (up to 90 mV) or long-lasting prepulses (up to 200 ms), tail current amplitudes and decay times were equally increased in dysgenic myotubes expressing either YFP-CaV1.11860 or YFP-CaV1.11666, suggesting that the distal C-terminal domain was not required for depolarization-induced potentiation. Thus, our experiments do not support the existence of either biochemical or functional interactions between proximal CaV1.1 and the distal C terminus.

Immunoprecipitation

Cav1.2

C-terminus

Yellow fluorescent protein

Bimolecular fluorescence complementation

10.1085/jgp.201411292

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Citations (4)

Multiple Regions Inhibit Expression of Cav1.1 Ca2+ Channels in Non-Muscle Cells

Biophysical Journal (2014)

Alexander Polster Tsutomu Tanabe Ong Moua Kurt G. Beam

Cav1.2

HEK 293 cells

10.1016/j.bpj.2013.11.795

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The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes

Proceedings of the National Academy of Sciences (2007)

Janet M. Wenzlau Kirstine Juhl Liping Yu Ong Moua Suparna A. Sarkar

Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic beta cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.

Prediabetes

10.1073/pnas.0705894104

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Citations (978)

Testing for Direct Interactions Between the DHPR and the RyR1 Cytoplasmic Foot

Biophysical Journal (2014)

Hicham Bichraoui Ong Moua Alexander Polster Tsutomu Tanabe Simon Papadopoulos

10.1016/j.bpj.2013.11.794

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Citations (0)

Junctional trafficking and restoration of retrograde signaling by the cytoplasmic RyR1 domain

The Journal of General Physiology (2017)

Alexander Polster Stefano Perni Dilyana Filipova Ong Moua Joshua D. Ohrtman

The type 1 ryanodine receptor (RyR1) in skeletal muscle is a homotetrameric protein that releases Ca2+ from the sarcoplasmic reticulum (SR) in response to an “orthograde” signal from the dihydropyridine receptor (DHPR) in the plasma membrane (PM). Additionally, a “retrograde” signal from RyR1 increases the amplitude of the Ca2+ current produced by CaV1.1, the principle subunit of the DHPR. This bidirectional signaling is thought to depend on physical links, of unknown identity, between the DHPR and RyR1. Here, we investigate whether the isolated cytoplasmic domain of RyR1 can interact structurally or functionally with CaV1.1 by producing an N-terminal construct (RyR11:4300) that lacks the C-terminal membrane domain. In CaV1.1-null (dysgenic) myotubes, RyR11:4300 is diffusely distributed, but in RyR1-null (dyspedic) myotubes it localizes in puncta at SR–PM junctions containing endogenous CaV1.1. Fluorescence recovery after photobleaching indicates that diffuse RyR11:4300 is mobile, whereas resistance to being washed out with a large-bore micropipette indicates that the punctate RyR11:4300 stably associates with PM–SR junctions. Strikingly, expression of RyR11:4300 in dyspedic myotubes causes an increased amplitude, and slowed activation, of Ca2+ current through CaV1.1, which is almost identical to the effects of full-length RyR1. Fast protein liquid chromatography indicates that ∼25% of RyR11:4300 in diluted cytosolic lysate of transfected tsA201 cells is present in complexes larger in size than the monomer, and intermolecular fluorescence resonance energy transfer implies that RyR11:4300 is significantly oligomerized within intact tsA201 cells and dyspedic myotubes. A large fraction of these oligomers may be homotetramers because freeze-fracture electron micrographs reveal that the frequency of particles arranged like DHPR tetrads is substantially increased by transfecting RyR-null myotubes with RyR11:4300. In summary, the RyR1 cytoplasmic domain, separated from its SR membrane anchor, retains a tendency toward oligomerization/tetramerization, binds to SR–PM junctions in myotubes only if CaV1.1 is also present and is fully functional in retrograde signaling to CaV1.1.

10.1085/jgp.201711879

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Citations (3)