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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

MRP4 Modulation of the Guanylate Cyclase-C/cGMP Pathway: Effects on Linaclotide-Induced Electrolyte Secretion and cGMP Efflux

Boris Tchernychev, Pei Ge, Marco M. Kessler, Robert M. Solinga, Derek Wachtel, Jenny V. Tobin, Sara R. Thomas, Craig E. Lunte, Angelika Fretzen, Gerhard Hannig, Alexander P. Bryant, Caroline B. Kurtz, Mark G. Currie and Inmaculada Silos-Santiago
Journal of Pharmacology and Experimental Therapeutics October 2015, 355 (1) 48-56; DOI: https://doi.org/10.1124/jpet.115.224329
Boris Tchernychev
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Pei Ge
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Marco M. Kessler
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Robert M. Solinga
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Derek Wachtel
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Jenny V. Tobin
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Sara R. Thomas
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Craig E. Lunte
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Angelika Fretzen
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Gerhard Hannig
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Alexander P. Bryant
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Caroline B. Kurtz
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Mark G. Currie
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Inmaculada Silos-Santiago
Ironwood Pharmaceuticals, Cambridge, Massachusetts (B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., A.F., G.H., A.P.B., C.B.K., M.G.C., I.S.-S.); and Ralph N. Adams Institute for Bioanalytical Chemistry, Department of Chemistry, University of Kansas, Lawrence, Kansas (S.R.T., C.E.L.)
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Abstract

MRP4 mediates the efflux of cGMP and cAMP and acts as an important regulator of these secondary messengers, thereby affecting signaling events mediated by cGMP and cAMP. Immunofluorescence staining showed high MRP4 expression localized predominantly in the apical membrane of rat colonic epithelium. In vitro studies were performed using a rat colonic mucosal layer mounted in an Ussing chamber. Linaclotide activation of the guanylate cyclase-C (GC-C)/cGMP pathway induced a concentration-dependent increase in transepithelial ion current [short-circuit current (Isc)] across rat colonic mucosa (EC50: 9.2 nM). Pretreatment of colonic mucosa with the specific MRP4 inhibitor MK571 potentiated linaclotide-induced electrolyte secretion and augmented linaclotide-stimulated intracellular cGMP accumulation. Notably, pretreatment with the phosphodiesterase 5 inhibitor sildenafil increased basal Isc, but had no amplifying effect on linaclotide-induced Isc. MRP4 inhibition selectively affected the activation phase, but not the deactivation phase, of linaclotide. In contrast, incubation with a GC-C/Fc chimera binding to linaclotide abrogated linaclotide-induced Isc, returning to baseline. Furthermore, linaclotide activation of GC-C induced cGMP secretion from the apical and basolateral membranes of colonic epithelium. MRP4 inhibition blocked cGMP efflux from the apical membrane, but not the basolateral membrane. These data reveal a novel, previously unrecognized mechanism that functionally couples GC-C-induced luminal electrolyte transport and cGMP secretion to spatially restricted, compartmentalized regulation by MRP4 at the apical membrane of intestinal epithelium. These findings have important implications for gastrointestinal disorders with symptoms associated with dysregulated fluid homeostasis, such as irritable bowel syndrome with constipation, chronic idiopathic constipation, and secretory diarrhea.

Footnotes

    • Received April 22, 2015.
    • Accepted July 24, 2015.
  • B.T., P.G., M.M.K., R.M.S., D.W., J.V.T., G.H., A.P.B., C.B.K., M.G.C., and I.S.-S. are employees and stockholders of Ironwood Pharmaceuticals, Inc. S.R.T. and C.E.L. received research support from Ironwood Pharmaceuticals, Inc.

  • dx.doi.org/10.1124/jpet.115.224329.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 355 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 355, Issue 1
1 Oct 2015
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

MRP4 Modulates GC-C-Dependent Electrolyte and cGMP Secretion

Boris Tchernychev, Pei Ge, Marco M. Kessler, Robert M. Solinga, Derek Wachtel, Jenny V. Tobin, Sara R. Thomas, Craig E. Lunte, Angelika Fretzen, Gerhard Hannig, Alexander P. Bryant, Caroline B. Kurtz, Mark G. Currie and Inmaculada Silos-Santiago
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 48-56; DOI: https://doi.org/10.1124/jpet.115.224329

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

MRP4 Modulates GC-C-Dependent Electrolyte and cGMP Secretion

Boris Tchernychev, Pei Ge, Marco M. Kessler, Robert M. Solinga, Derek Wachtel, Jenny V. Tobin, Sara R. Thomas, Craig E. Lunte, Angelika Fretzen, Gerhard Hannig, Alexander P. Bryant, Caroline B. Kurtz, Mark G. Currie and Inmaculada Silos-Santiago
Journal of Pharmacology and Experimental Therapeutics October 1, 2015, 355 (1) 48-56; DOI: https://doi.org/10.1124/jpet.115.224329
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