Endogenous cellular prion protein regulates contractility of the mouse ileum

Authors

  • G. R. MARTIN,

    1. Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
    2. Department of Biochemistry and Molecular Biology and The McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, Alberta, Canada
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  • A. L. ALVAREZ,

    1. Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
    2. Department of Biochemistry and Molecular Biology and The McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, Alberta, Canada
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    • Contributed equally.

  • M. BASHASHATI,

    1. Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
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    • Contributed equally.

  • C. M. KEENAN,

    1. Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
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  • F. R. JIRIK,

    1. Department of Biochemistry and Molecular Biology and The McCaig Institute for Bone & Joint Health, University of Calgary, Calgary, Alberta, Canada
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  • K. A. SHARKEY

    1. Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada
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Address for Correspondence
Gary R. Martin or Keith A. Sharkey, Department of Physiology and Pharmacology, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada.
Tel: 403-220-5880; fax: 403-270-3353;
e-mail: marting@ucalgary.ca or ksharkey@ucalgary.ca

Abstract

Background  Cellular prion protein (PrPC) is expressed in the enteric nervous system (ENS), however, its physiological role has not been identified. Studies suggest that PrPC can function as a metal-binding protein, as absence of the protein has been linked to altered copper metabolism and atypical synaptic activity. Because copper is known to modulate smooth muscle relaxation, we tested the hypothesis that PrPC deficiency would alter intestinal contractility.

Methods  We examined electrically evoked ileal contractility in Prnp−/− or wild type littermate mice and the effects of copper or copper chelation. PrPC expression was studied in whole mount ileal preparations of mice and guinea pigs by immunohistochemistry.

Key Results  Relative to wild type mice, ileal tissues of Prnp−/− mice exhibited reduced electrical field stimulation (EFS)-evoked contractility. Furthermore, EFS-induced relaxation, as a percentage of that induced by a nitric oxide donor, was enhanced. Addition of a copper donor to the organ bath increased, whereas the addition of a copper chelator inhibited, nitric oxide donor-induced ileal relaxation in Prnp−/− mice. PrPC was expressed on nerve fibers or terminals, and some cell bodies in the myenteric and submucosal plexuses of wild type mice. PrPC colocalized with a neuron-specific ectonucleotidase, nucleoside triphosphate diphosphohydrolase 3 (NTPDase3), but to only a limited extent with GFAP, a marker of enteric glia. Guinea pigs expressed PrPC in nerve fibers or terminals and enteric glia in the myenteric and submucosal plexuses.

Conclusions & Inferences  Our findings suggest that PrPC, which is abundant in the ENS, has a role in the regulation of ileal contractility.

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