K M Sanders

University of Nevada, Reno, Reno, Nevada, United States

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Publications (418)2257.8 Total impact

  • Kenton M Sanders · Sean M Ward · Andreas Friebe

    No preview · Article · Feb 2016 · The Journal of Physiology
  • Kenton M Sanders · Sean M Ward · Andreas Friebe

    No preview · Article · Feb 2016 · The Journal of Physiology

  • No preview · Article · Feb 2016 · The Journal of Physiology
  • Sung Jin Hwang · Naseer Basma · Kenton M. Sanders · Sean M. Ward
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    ABSTRACT: Background and purpose: High-throughput screening of compound libraries using genetically encoded fluorescent biosensors has identified several 2nd. generation small-molecule calcium-activated chloride channel (CaCC Ano1) inhibitors. The purpose of this study was to (i) examine the effects of these Ano1 inhibitors on gastric and intestinal pacemaker activity, (ii) compare the effects of these inhibitors with the more classical CaCC inhibitor, NPPB, (ii) examine the mode of action of these compounds on the waveform of pacemaker activity and (iii) compare differences in the sensitivity between gastric and intestinal pacemaker activity to these CaCC Ano1 inhibitors. Experimental approach: Using intracellular microelectrode recordings of gastric and intestinal muscle preparations the dose dependent effects of 2nd. generation CaCC Ano1 inhibitors were examined on spontaneous electrical slow waves. Key results: There were significant differences in the efficacy of 2nd. generation CaCC Ano1 inhibitors on gastric and intestinal pacemaker activity. Antral slow waves were more sensitive to CaCC Ano1 inhibitors than intestinal slow waves. CaCCinh -A01 and benzbromorone were the most potent at inhibiting slow waves in both muscle preparations and more sensitive than NPPB. Dichlorophene and hexachlorophene were equally potent at inhibiting slow waves. Surprisingly, slow waves were relatively insensitive to T16Ainh -A01 in both preparations. Conclusions and implications: The present study identifies several 2nd. generation CaCC Ano1 inhibitors that blocked gastric and intestinal pacemaker activity. Differences in the sensitivity of CaCC Ano1 antagonists between these two organs suggest the possibility of different splice variants in stomach and intestine or the involvement of other conductances in the generation and propagation of pacemaker activity in these gastrointestinal organs. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · British Journal of Pharmacology
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    ABSTRACT: Serum response factor (SRF) is a transcription factor known to mediate phenotypic plasticity in smooth muscle cells (SMCs). Despite the critical role of this protein in mediating intestinal injury response, little is known about the mechanism through which SRF alters SMC behavior. Here, we provide compelling evidence for the involvement of SRF-dependent microRNAs (miRNAs) in the regulation of SMC apoptosis. We generated SMC-restricted Srf inducible knockout (KO) mice and observed both severe degeneration of SMCs and a significant decrease in the expression of apoptosis-associated miRNAs. The absence of these miRNAs was associated with overexpression of apoptotic proteins, and we observed a high level of SMC death and myopathy in the intestinal muscle layers. These data provide a compelling new model that implicates SMC degeneration via anti-apoptotic miRNA deficiency caused by lack of SRF in gastrointestinal motility disorders.
    Full-text · Article · Dec 2015 · Cell Death & Disease
  • Kenton M. Sanders · Kathleen D. Keef

    No preview · Article · Oct 2015 · The Journal of Physiology
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    Violeta N. Mutafova-Yambolieva · Kenton M. Sanders

    Full-text · Article · Oct 2015 · AJP Gastrointestinal and Liver Physiology
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    Kenton M Sanders · Grant Hennig

    Preview · Article · Oct 2015 · Journal of neurogastroenterology and motility
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    ABSTRACT: Background/aims: Smooth muscle cells (SMCs) characteristically express serum response factor (SRF), which regulates their development. The role of SRF in SMC plasticity in the pathophysiological conditions of gastrointestinal (GI) tract is less characterized. Methods: We generated SMC-specific Srf knockout mice and characterized the prenatally lethal phenotype using ultrasound biomicroscopy and histological analysis. We used small bowel partial obstruction surgeries and primary cell culture using cell-specific enhanced green fluorescent protein (EGFP) mouse lines to study phenotypic and molecular changes of SMCs by immunofluorescence, Western blotting, and quantitative polymerase chain reaction. Finally we examined SRF change in human rectal prolapse tissue by immunofluorescence. Results: Congenital SMC-specific Srf knockout mice died before birth and displayed severe GI and cardiac defects. Partial obstruction resulted in an overall increase in SRF protein expression. However, individual SMCs appeared to gradually lose SRF in the hypertrophic muscle. Cells expressing low levels of SRF also expressed low levels of platelet-derived growth factor receptor alpha (PDGFRα(low)) and Ki67. SMCs grown in culture recaptured the phenotypic switch from differentiated SMCs to proliferative PDGFRα(low) cells. The immediate and dramatic reduction of Srf and Myh11 mRNA expression confirmed the phenotypic change. Human rectal prolapse tissue also demonstrated significant loss of SRF expression. Conclusions: SRF expression in SMCs is essential for prenatal development of the GI tract and heart. Following partial obstruction, SMCs down-regulate SRF to transition into proliferative PDGFRα(low) cells that may represent a phenotype responsible for their plasticity. These findings demonstrate that SRF also plays a critical role in the remodeling process following GI injury.
    Full-text · Article · Oct 2015 · Journal of neurogastroenterology and motility
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    ABSTRACT: Telokin phosphorylation by cyclic GMP-dependent protein kinase facilitates smooth muscle relaxation. In this study we examined the relaxation of gastric fundus smooth muscles from basal tone, or pre-contracted with KCl or carbachol (CCh), and the phosphorylation of telokin S13, myosin light chain (MLC) S19, MYPT1 T853, T696, and CPI-17 T38 in response to 8-Bromo-cGMP, the NO donor sodium nitroprusside (SNP), or nitrergic neurotransmission. We compared MLC phosphorylation and the contraction and relaxation responses of gastric fundus smooth muscles from telokin-/- mice and their wild-type littermates to KCl or CCh, and 8-Bromo-cGMP, SNP, or nitrergic neurotransmission, respectively. We compared the relaxation responses and telokin phosphorylation of gastric fundus smooth muscles from wild-type mice and W/WV mice which lack ICC-IM, to 8-Bromo-cGMP, SNP, or nitrergic neurotransmission. We found that telokin S13 is basally phosphorylated and that 8-Bromo-cGMP and SNP increased basal telokin phosphorylation. In muscles pre-contracted with KCl or CCh, 8-Bromo-cGMP and SNP had no effect on CPI-17 or MYPT1 phosphorylation, but increased telokin phosphorylation and reduced MLC phosphorylation. In telokin-/- gastric fundus smooth muscles, basal tone and constitutive MLC S19 phosphorylation were increased. Pre-contracted telokin-/- gastric fundus smooth muscles have increased contractile responses to KCl, CCh, or cholinergic neurotransmission and reduced relaxation to 8-Bromo-cGMP, SNP, and nitrergic neurotransmission. However, basal telokin phosphorylation was not increased when muscles were stimulated with lower concentrations of SNP or when the muscles were stimulated by nitrergic neurotransmission. SNP, but not nitrergic neurotransmission, increased telokin Ser13 phosphorylation in both wild-type and W/WV gastric fundus smooth muscles. Our findings indicate that telokin may play a role in attenuating constitutive MLC phosphorylation and provide an additional mechanism to augment gastric fundus mechanical responses to inhibitory neurotransmission.
    Full-text · Article · Aug 2015 · PLoS ONE
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    ABSTRACT: Genome-scale expression data on the absolute numbers of gene isoforms offers essential clues in cellular functions and biological processes. Smooth muscle cells (SMCs) perform a unique contractile function through expression of specific genes controlled by serum response factor (SRF), a transcription factor that binds to DNA sites known as the CArG boxes. To identify SRF-regulated genes specifically expressed in SMCs, we isolated SMC populations from mouse small intestine and colon, obtained their transcriptomes, and constructed an interactive SMC genome and CArGome browser. To our knowledge, this is the first online resource that provides a comprehensive library of all genetic transcripts expressed in primary SMCs. The browser also serves as the first genome-wide map of SRF binding sites. The browser analysis revealed novel SMC-specific transcriptional variants and SRF target genes, which provided new and unique insights into the cellular and biological functions of the cells in gastrointestinal (GI) physiology. The SRF target genes in SMCs, which were discovered in silico, were confirmed by proteomic analysis of SMC-specific Srf knockout mice. Our genome browser offers a new perspective into the alternative expression of genes in the context of SRF binding sites in SMCs and provides a valuable reference for future functional studies.
    Full-text · Article · Aug 2015 · PLoS ONE
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    ABSTRACT: Purines induce transient contraction and prolonged relaxation of detrusor muscles. Transient contraction is likely due to activation of inward currents in smooth muscle cells, and prolonged relaxation may be due to activation of small conductance Ca(2+)-activated K(+) (SK) channels via P2Y1 receptors expressed by detrusor PDGFRα(+) cells. We investigated whether other subtypes of P2Y receptors are involved in the activation of SK channels in PDGFRα(+) cells of detrusor muscles. Quantitative analysis of transcripts revealed that P2ry2, P2ry4 and P2ry14 are expressed in PDGFRα(+) cells of P2ry1-/- /eGFP mice at similar levels as in wild type mice. UTP, a P2Y2/P2Y4 agonist, activated large outward currents in detrusor PDGFRα(+) cells. SK channel blockers and an inhibitor of phospholipase C completely abolished currents activated by UTP. In contrast, UTP activated non-selective cation currents in smooth muscle cells. Under current-clamp (I=0), UTP induced significant hyperpolarization of PDGFRα(+) cells. MRS2500, a P2Y1 antagonist, did not affect the UTP-activated outward currents in PDGFRα(+) cells from wild type, and activation of outward currents by UTP was retained in P2ry1-/-/eGFP mice. As a negative control, we tested the effect of MRS2693, a selective P2Y6 agonist. This compound did not activate outward currents in PDGFRα(+) cells, and currents activated by UTP were unaffected by MRS2578, a selective P2Y6 antagonist. Nonselective P2Y receptor blocker inhibited UTP-activated outward currents in PDGFRα(+) cells. Our data demonstrate that P2Y2 and/or P2Y4 receptors function, in addition to P2Y1 receptors in activating SK currents in PDGFRα(+) cells and possibly in mediating purinergic relaxation in detrusor muscles. Copyright © 2015, American Journal of Physiology - Renal Physiology.
    No preview · Article · Jul 2015 · AJP Renal Physiology
  • Kenton M Sanders

    No preview · Article · Jun 2015 · Gastroenterology
  • Bernard T. Drumm · Salah A. Baker · Grant W. Hennig · Kenton M. Sanders
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    ABSTRACT: Interstitial cells of Cajal in the deep muscular plexus of the small intestine (ICC-DMP) are closely associated with varicosities of enteric motor neurons and generate responses contributing to neural regulation of intestinal motility. Responses of ICC-DMP are mediated by activation of Ca2+-activated Cl− channels, thus Ca2+ signaling is central to the behaviours of these cells. Confocal imaging was used to characterize the nature and mechanisms of Ca2+ transients in ICC-DMP within intact jejunal muscles expressing GCaMP3 selectively in ICC. ICC-DMP displayed spontaneous Ca2+ transients that ranged from discrete, localized events to waves that propagated over variable distances. The occurrence of Ca2+ transients was highly variable, and it was determined that firing was stochastic in nature. Ca2+ transients were tabulated in multiple cells within fields of view, and no correlation was found between the events in adjacent cells. Tetrodotoxin (1 μm) significantly increased the occurrence of Ca2+ transients, suggesting that ICC-DMP contribute to the tonic inhibition conveyed by ongoing activity of inhibitory motor neurons. Ca2+ transients were minimally affected after 12 min in Ca2+ free solution, indicating these events do not depend immediately upon Ca2+ influx. However, inhibitors of SERCA and blockers of inositol triphosphate receptor (InsP3R) and ryanodine receptor (RyR) channels blocked ICC Ca2+ transients. These data suggest interdependence between RyR and InsP3R in the generation of Ca2+ transients. Itpr1 and Ryr2 were the dominant transcripts expressed by ICC. These findings provide the first high-resolution recording of the subcellular Ca2+ dynamics that control the behaviour of ICC-DMP in situ. This article is protected by copyright. All rights reserved
    No preview · Conference Paper · May 2015
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    ABSTRACT: In cerebral artery myocytes, close proximity of the sarcoplasmic reticulum (SR) and plasma membrane (PM) creates microdomains where Ca2+ released from the SR attains a concentration sufficient to activate large-conductance Ca2+-activated K+ (BK) and melastatin transient receptor potential 4 (TRPM4) channels; essential regulators of membrane excitability. Microtubules organize the SR in cardiac and skeletal muscle cells, but it is not known if they serve this function in smooth muscle cells. Here, we test the hypothesis that microtubules maintain the SR architecture forming Ca2+ microdomains essential for BK and TRPM4 channel activity. Using membrane- and tubulin-specific fluorescent dyes, we observed distinct microtubule arches beneath the peripheral SR proximal to the PM in contractile cerebral artery smooth muscle cells. Nocodazole, an inhibitor of microtubule polymerization, disrupted these subcellular structures and increased the distance between the SR and PM. Using high-speed, high-resolution confocal Ca2+ imaging, we found that microtubule depolymerization altered the spatiotemporal properties of localized Ca2+ signaling events. Nocodazole treatment also resulted in the loss of Ca2+-dependent TRPM4 and BK channel activity in perforated whole-cell patch clamp recordings and diminished contractility in pressure myography experiments. We conclude that the microtubule network is essential for maintaining the SR architecture and Ca2+ microdomains necessary for the activation of BK and TRPM4 channels in cerebral artery myocytes.
    No preview · Conference Paper · Apr 2015
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    Kenton M Sanders · Sean M Ward · Sang Don Koh

    Full-text · Article · Apr 2015 · Physiological Reviews
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    ABSTRACT: Gastric peristalsis begins in the orad corpus and propagates to the pylorus. Directionality of peristalsis depends upon orderly generation and propagation of electrical slow waves and a frequency gradient between proximal and distal pacemakers. We sought to understand how chronotropic agonists affect coupling between corpus and antrum. Electrophysiological and imaging techniques were used to investigate regulation of gastric slow wave frequency by muscarinic agonists in mice. We also investigated the expression and role of cholinesterases in regulating slow wave frequency and motor patterns in the stomach. Both acetycholinesterase (Ache) and butyrylcholine esterase (Bche) are expressed in gastric muscles and AChE is localized to var-icose processes of motor neurons. Inhibition of AChE in the absence of stimulation increased slow wave frequency in corpus and throughout muscle strips containing corpus and antrum. CCh caused depolarization and increased slow wave frequency. Stimulation of cholinergic neurons increased slow wave frequency but did not cause depolarization. Neostigmine (1 μM) in-creased slow wave frequency, but uncoupling between corpus and antrum was not detected. Motility mapping of contractile activity in gastric muscles showed similar effects of enteric nerve stimulation on the frequency and propagation of slow waves, but neostigmine (> 1 μM) caused aberrant contractile frequency and propagation and ectopic pacemaking. Our data show that slow wave uncoupling is difficult to assess with electrical recording from a single or double sites and sug-gest that efficient metabolism of ACh released from motor neurons is an extremely important regulator of slow wave frequency and propagation and gastric motility patterns.
    Full-text · Article · Mar 2015 · Journal of neurogastroenterology and motility
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    ABSTRACT: Growing evidence suggests important roles for specialized platelet-derived growth factor-alpha-positive (PDGFRalpha(+)) cells in regulating the behaviors of visceral smooth muscle organs. Examination of the female reproductive tracts of mice and monkeys showed that PDGFRalpha(+) cells form extensive networks in ovary, oviduct and uterus. PDGFRalpha(+) cells were located in discrete locations within these organs and their distribution and density was similar in rodents and primates. PDGFRalpha(+) cells were distinct from smooth muscle cells and interstitial cells of Cajal (ICC). This was demonstrated with immunohistochemical techniques and by performing molecular expression studies on PDGFRalpha(+) cells from mice with eGFP driven off the endogenous promoter for Pdgfralpha. Significant differences in gene expression were found in PDGFRalpha(+) cells from ovary, oviduct and uterus. Differences in gene expression were also detected in cells from different tissue regions within the same organ (e.g. uterine myometrium vs. endometrium). PDGFRalpha(+) cells are unlikely to provide pacemaker activity because they lacked significant expression of key pacemaker genes found in ICC (Kit and Ano1). Gja1 encoding connexin 43 was expressed at relatively high levels in PDGFRalpha(+) cells (except ovary) suggesting these cells can form gap junctions to one another and neighboring smooth muscle cells. PDGFRalpha(+) cells also expressed the early response transcription factor and proto-oncogene c-Fos, particularly in the ovary. These data demonstrate extensive distribution of PDGFRalpha(+) cells throughout the female reproductive tract. These cells are a heterogeneous population of cells that are likely to contribute to different aspects of physiological regulation in the various anatomical niches they occupy. Copyright 2015 by The Society for the Study of Reproduction.
    No preview · Article · Mar 2015 · Biology of Reproduction
  • Byoung Koh · Lauren Peri · Haeyeong Lee · Kenton Sanders · Sang Don Koh

    No preview · Conference Paper · Feb 2015
  • Haeyeong Lee · Byoung Koh · Lauren Peri · Kenton Sanders · Sang Don Koh

    No preview · Conference Paper · Feb 2015

Publication Stats

18k Citations
2,257.80 Total Impact Points

Institutions

  • 1988-2016
    • University of Nevada, Reno
      • • Department of Physiology and Cell Biology
      • • School of Medicine
      Reno, Nevada, United States
  • 1984-2015
    • University of Nevada School of Medicine
      • Department of Pharmacology
      Reno, Nevada, United States
  • 2009
    • University of Auckland
      Окленд, Auckland, New Zealand
  • 2004
    • Australian National University
      Canberra, Australian Capital Territory, Australia
  • 1996
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States
  • 1995
    • University of California, Davis
      Davis, California, United States
    • Baylor College of Medicine
      Houston, Texas, United States
  • 1992
    • St. James's Hospital
      • MedEl Directorate
      Dublin, Leinster, Ireland