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Research ArticleArticle

Progression from Homologous to Heterologous Desensitization of Contraction in Gastric Smooth Muscle Cells

Carola Severi, Veronica Carnicelli, Antonio di Giulio, Giovanna Romano, Argante Bozzi, Arduino Oratore, Roberto Strom and Gianfranco Delle Fave
Journal of Pharmacology and Experimental Therapeutics February 1999, 288 (2) 389-398;
Carola Severi
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Veronica Carnicelli
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Antonio di Giulio
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Giovanna Romano
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Argante Bozzi
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Arduino Oratore
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Roberto Strom
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Gianfranco Delle Fave
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Abstract

Acute desensitization of contraction and its relative mechanisms have been studied in smooth muscle cells isolated from guinea pig stomach. Desensitization was induced by pre-exposure of the cells to one of the excitatory neuropeptides linked to the phospholipase C intracellular cascade, i.e., cholecystokinin (CCK), gastrin-releasing peptide, and Substance P. Desensitization was homologous after a 30-s pre-exposure and heterologous if pre-exposure lasted for 5 min or longer. Homologous desensitization was studied in a more detailed way after pre-exposure to CCK. Preincubation with increasing concentrations of CCK (10 pM–1 μM) induced a progressive rightward shift of the dose-response curves associated with both a decrease in potency (ED50 4.5 pM–2.2 nM) and a maximum response that were not related to a modification of response kinetics. After brief pre-exposure to 1 nM CCK (Dmax), an inhibition of contraction was observed in response to an identical dose of CCK (45.1 ± 8.6%), the decreased response being associated with an inhibition of inositol phosphates and [Ca++]imobilization. Both inositol trisphosphate (InsP3)-induced contraction and [Ca++]i mobilization were inhibited to a lesser extent than CCK-induced responses. Any longer pre-exposure of cells to one of the above-mentioned neuropeptides caused heterologous desensitization, with an observed inhibition of contraction in response to all tested agonists (CCK, 60.3 ± 5.9%; gastrin-releasing peptide: 56.7 ± 3.5%; Substance P, 60.6 ± 6.5%). A similar decrease was observed in InsP3-induced contractions resulting in a desensitization of the InsP3 response as well. Full recovery of contractile responses appeared within 30 min from the end of preincubation, thus indicating that degradation of membrane receptors did not occur. Although pre-exposure of the cells to protein kinase C inhibitor GF109203X did not modify CCK-induced homologous desensitization, it blocked CCK-induced heterologous desensitization. This study demonstrates that excitatory phospholipase C-coupled enteric neuropeptides induce a time-dependent homologous as well as heterologous desensitization of smooth muscle contraction occurring at receptor and postreceptor levels.

Footnotes

  • Send reprint requests to: Carola Severi, Gastroenterology Unit 1, Clinica Medica 2, Policlinico Umberto I, Viale del Policlinico, 00161 Rome, Italy. E-mail: digiulio{at}aquila.infn.it

  • ↵1 This work was supported by grants from the Ministero dell’Università e della Ricerca Scientifica (MURST 60%) assigned to the Universities of L’Aquila and Rome.

  • Abbreviations:
    CCK
    cholecystokinin
    DAG
    1,2-diacylglycerol
    Fura-2-AM
    1-[2-carboxyoxazol-2yl)-6-aminobenzofuran-5-oxyl]-2-(2′-amino-5′-methylphenoxy)-ethane-N,N,N′,N′-tetraacetic acid, sodium salt
    GF109203X
    2-[1-(3-dimethylaminopropyl)-1H-indol-3yl]-3-(1H-indol-3-yl) maleimide
    GRP
    gastrin-releasing peptide
    InsPs
    inositol phosphate(s)
    InsP3
    inositol trisphosphate
    PKC
    protein kinase C
    PLC
    phospholipase C
    SP
    substance P
    • Received January 2, 1998.
    • Accepted August 4, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 2
1 Feb 1999
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Research ArticleArticle

Progression from Homologous to Heterologous Desensitization of Contraction in Gastric Smooth Muscle Cells

Carola Severi, Veronica Carnicelli, Antonio di Giulio, Giovanna Romano, Argante Bozzi, Arduino Oratore, Roberto Strom and Gianfranco Delle Fave
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 389-398;

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Research ArticleArticle

Progression from Homologous to Heterologous Desensitization of Contraction in Gastric Smooth Muscle Cells

Carola Severi, Veronica Carnicelli, Antonio di Giulio, Giovanna Romano, Argante Bozzi, Arduino Oratore, Roberto Strom and Gianfranco Delle Fave
Journal of Pharmacology and Experimental Therapeutics February 1, 1999, 288 (2) 389-398;
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