K M Sanders

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

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Publications (483)

  • Lara Alex Shaylor · Sung Jin Hwang · Kenton M Sanders · Sean M Ward
    [Show abstract] [Hide abstract] ABSTRACT: Inhibitory motor neurons regulate several gastric motility patterns including receptive relaxation, gastric peristaltic motor patterns and pyloric sphincter opening. Nitric oxide (NO) and purines have been identified as likely candidates that mediate inhibitory neural responses. However, the contribution from each neurotransmitter has received little attention in the distal stomach. The aims of this study were to identify the roles played by NO and purines in inhibitory motor responses in the antrums of mice and monkeys. By using wildtype mice and mutants with genetically deleted neural nitric oxide synthase (Nos1(-/-)) and P2Y1 receptors (P2ry1(-/-)) we examined the roles of NO and purines in post-junctional inhibitory responses in the distal stomach and compared these responses to those in primate stomach. Activation of inhibitory motor nerves using electrical field stimulation (EFS) produced frequency-dependent inhibitory junction potentials (IJPs) that produced muscle relaxations in both species. Stimulation of inhibitory nerves during slow waves terminated pacemaker events and associated contractions. In Nos1(-/-) mice IJPs and relaxations persisted whereas in P2ry1(-/-) mice IJPs were absent but relaxations persisted. In the gastric antrum of the non-human primate model Macaca fascicularis, similar NO and purine neural components contributed to inhibition of gastric motor activity. These data support a role of convergent inhibitory neural responses in the regulation of gastric motor activity across diverse species.
    Article · Sep 2016 · AJP Gastrointestinal and Liver Physiology
  • Kenton M. Sanders · Yoshihiko Kito · Sung Jin Hwang · Sean M. Ward
    [Show abstract] [Hide abstract] ABSTRACT: Interstitial cells of mesenchymal origin form gap junctions with smooth muscle cells in visceral smooth muscles and provide important regulatory functions. In gastrointestinal (GI) muscles, there are two distinct classes of interstitial cells, c-Kit+ interstitial cells of Cajal and PDGFRα+ cells, that regulate motility patterns. Loss of these cells may contribute to symptoms in GI motility. disorders.
    Article · Sep 2016 · Physiology
  • Tae Sik Sung · Kate O'Driscoll · Haifeng Zheng · [...] · Kenton M Sanders
    [Show abstract] [Hide abstract] ABSTRACT: Anoctamin-1 (ANO1) is a Ca(2+)-activated Cl(-) channel expressed in many types of cells. Splice variants of ANO1 have been shown to influence the biophysical properties of the conductance. Several new antagonists of ANO1 with relatively high affinity and selectivity have been suggested to have usefulness for experimental and potentially for therapeutic purposes. We investigated the effects of intracellular Ca(2+) (100-1000 nM), a concentration range that might be achieved in cells during physiological activation of ANO1 channels, on the block of ANO1 channels expressed in HEK 293 cells. Tests were performed on a variety of naturally occurring splice variants of ANO1 using whole cell and excised patch configurations of the patch clamp technique. Block of ANO1 currents with aminophenylthiazole (T16Ainh-A01) was highly dependent upon [Ca(2+)]i Increasing [Ca(2+)]i reduced the potency of this blocker. Similar Ca(2+)-dependent effects were also observed with benzbromarone. Experiments on excised, inside-out patches showed that the diminished potency of the blockers caused by intracellular Ca(2+) might involve a competitive interaction for a common binding site or repulsion of the blocking drugs by electrostatic forces at the cytoplasmic surface of the channels. The degree of interaction between the channel blockers and [Ca(2+)]i depended upon the splice variant expressed. These experiments demonstrate that the efficacy of ANO1 antagonists depends upon [Ca(2+)]i, suggesting a need for caution when using ANO1 blockers to determine the role of ANO1 in physiological functions and in use as therapeutic agents.
    Article · Jul 2016 · AJP Cell Physiology
  • [Show abstract] [Hide abstract] ABSTRACT: The pacemaker function of interstitial cells of Cajal (ICC) is impaired during intestinal inflammation. The aim of this study is to clarify the pathophysiological mechanisms of ICC dysfunction during inflammatory condition by using intestinal cell clusters. Cell clusters were prepared from smooth muscle layer of murine jejunum and treated with interferon-gamma and lipopolysaccharide (IFN-γ+LPS) for 24h to induce inflammation. Pacemaker function of ICC was monitored by measuring cytosolic Ca(2+) oscillation in the presence of nifedipine. Treatment with IFN-γ+LPS impaired the pacemaker activity of ICC with increasing mRNA level of interleukin-1 beta, tumor necrosis factor-alpha and interleukin-6 in cell clusters; however, treatment with these cytokines individually had little effect on pacemaker activity of ICC. Treatment with IFN-γ+LPS also induced the expression of inducible nitric oxide synthase (iNOS) in smooth muscle cells and resident macrophages, but not in ICC. Pretreatment with NOS inhibitor, L-NAME or iNOS inhibitor, 1400W ameliorated IFN-γ+LPS-induced pacemaker dysfunction of ICC. Pretreatment with guanylate cyclase inhibitor, ODQ did not, but antioxidant, apocynin, to suppress NO-induced oxidative stress, significantly suppressed the impairment of ICC function induced by IFN-γ+LPS. Treatment with IFN-γ+LPS also decreased c-Kit-positive ICC, which was prevented by pretreatment with L-NAME. However, apoptotic ICC were not detected in IFN-γ+LPS-treated clusters, suggesting IFN-γ+LPS stimulation just changed the phenotype of ICC but not induced cell death. Moreover, ultrastructure of ICC was not disturbed by IFN-γ+LPS. In conclusion, ICC dysfunction during inflammation is induced by NO-induced oxidative stress rather than NO/cGMP signaling. NO-induced oxidative stress might be the main factor to induce phenotypic changes of ICC.
    Article · Jul 2016 · Pharmacological Research
  • Article · Apr 2016
  • Kenton M Sanders · Sean M Ward · Andreas Friebe
    Article · Feb 2016 · The Journal of Physiology
  • Kenton M Sanders · Sean M Ward · Andreas Friebe
    Article · Feb 2016 · The Journal of Physiology
  • Salah A. Baker · Bernard T. Drumm · Grant W. Hennig · [...] · Kenton M. Sanders
    Article · Feb 2016 · The Journal of Physiology
  • Conference Paper · Feb 2016
  • Sung Jin Hwang · Naseer Basma · Kenton M. Sanders · Sean M. Ward
    [Show abstract] [Hide abstract] 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.
    Article · Jan 2016 · British Journal of Pharmacology
  • Kenton M. Sanders
    [Show abstract] [Hide abstract] ABSTRACT: The idea of an inhibitory innervation in the gut came from Geoff Burnstock’s group at the University of Melbourne in the 1960s. Being resistant to antagonists of norepinephrine and acetylcholine, enteric inhibitory neurotransmission became known as non-cholinergic, non-adrenergic (NANC) neurotransmission. ATP (or a closely related nucleotide) was proposed as the inhibitory neurotransmitter based on release of purines during nerve stimulation and similarities between responses to ATP and transmural nerve stimulation in several gut preparations. Apamin was found to block purinergic responses, providing evidence that small-conductance Ca2+-activated K+ (SK) channels were responsible for inhibitory junction potentials (IJPs). Actually the IJPs in GI muscles are composed of multiple components, and later studies discovered nitric oxide (NO) to be the other major mediator of NANC inhibitory neurotransmission. The purinergic component of enteric inhibitory neurotransmission is mediated by P2Y1 receptors, and this component is absent in P2Y1−/− mice. The criteria for a neurotransmitter are better met by β-nicotinamide adenine dinucleotide (β-NAD) or its immediate metabolite ADP-ribose (ADPR) than by ATP. The cells mediating post-junctional responses have been identified. In addition to smooth muscle cells, two classes of interstitial cells express receptors and effectors for NANC neurotransmitters and are electrically coupled to smooth muscle cells. This integrated structure has been named the SIP syncytium. Interstitial cells of Cajal are involved in transduction of cholinergic and nitrergic inputs to GI muscles, and PDGFRα+ cells mediate purinergic effects. This short symposium report summarizes major historical points of interest and some of the more recent findings related to enteric inhibitory neurotransmission.
    Chapter · Jan 2016
  • T.S. Sung · K. O’Driscoll · H. Zheng · [...] · K.M. Sanders
    [Show abstract] [Hide abstract] ABSTRACT: Influence of intracellular Ca²⁺ and alternative splicing on the pharmacological profile of ANO1 channels. Am J Physiol Cell Physiol 311: C437-C451, 2016. First published July 13, 2016; doi:10.1152/ajpcell.00070.2016.—Anoctamin-1 (ANO1) is a Ca²⁺-activated Cl⁻ channel expressed in many types of cells. Splice variants of ANO1 have been shown to influence the biophysical properties of conductance. It has been suggested that several new antagonists of ANO1 with relatively high affinity and selectivity might be useful for experimental and, potentially, therapeutic purposes. We investigated the effects of intracellular Ca²⁺ concentration ([Ca²⁺]i) at 100-1,000 nM, a concentration range that might be achieved in cells during physiological activation of ANO1 channels, on blockade of ANO1 channels expressed in HEK-293 cells. Whole cell and excised patch configurations of the patch-clamp technique were used to perform tests on a variety of naturally occurring splice variants of ANO1. Blockade of ANO1 currents with aminophenylthiazole (T16Ainh-A01) was highly dependent on [Ca²⁺]i. Increasing [Ca²⁺]i reduced the potency of this blocker. Similar Ca²⁺-dependent effects were also observed with benzbromarone. Experiments on excised, inside-out patches showed that the diminished potency of the blockers caused by intracellular Ca²⁺ might involve a competitive interaction for a common binding site or repulsion of the blocking drugs by electrostatic forces at the cytoplasmic surface of the channels. The degree of interaction between the channel blockers and [Ca²⁺]i depends on the splice variant expressed. These experiments demonstrate that the efficacy of ANO1 antagonists depends on [Ca²⁺]i, suggesting a need for caution when ANO1 blockers are used to determine the role of ANO1 in physiological functions and in their use as therapeutic agents.
    Article · Jan 2016
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    C Park · MY Lee · O J Slivano · [...] · S Ro
    [Show abstract] [Hide abstract] 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
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    C Park · M Y Lee · O J Slivano · [...] · S Ro
    Full-text Dataset · Dec 2015
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    C Park · M Y Lee · O J Slivano · [...] · S Ro
    Full-text Dataset · Dec 2015
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    C Park · M Y Lee · O J Slivano · [...] · S Ro
    Full-text Dataset · Dec 2015
  • Kenton M. Sanders · Kathleen D. Keef
    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
    Full-text Article · Oct 2015 · Journal of neurogastroenterology and motility
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    [Show abstract] [Hide abstract] 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

Publication Stats

20k Citations

Institutions

  • 2001-2015
    • University of Nevada, Reno
      • Department of Physiology and Cell Biology
      Reno, Nevada, United States
  • 1995
    • Baylor College of Medicine
      Houston, Texas, United States
    • University of California, Davis
      Davis, California, United States
  • 1992
    • St. James's Hospital
      • MedEl Directorate
      Dublin, Leinster, Ireland
  • 1991
    • University of Nevada School of Medicine
      • Department of Pharmacology
      Reno, Nevada, United States