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OtherGASTROINTESTINAL PHARMACOLOGY

Differences in Partial Agonist Action at Cholecystokinin Receptors of Mouse and Rat Are Dependent on Parameters Extrinsic to Receptor Structure: Molecular Cloning, Expression and Functional Characterization of the Mouse Type A Cholecystokinin Receptor

D. Ghanekar, E. M. Hadac, E. L. Holicky and L. J. Miller
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1206-1212;
D. Ghanekar
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E. M. Hadac
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E. L. Holicky
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L. J. Miller
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Abstract

The mouse cholecystokinin (CCK) receptor is functionally distinct from the extensively studied rat receptor on the basis of differences in binding and biological activity of phenethyl ester analogs of CCK. These are partial agonists at the rat receptor and full agonists at the mouse pancreatic receptor. To explore this, we cloned the cDNA for the mouse type A CCK receptor, established a receptor-bearing Chinese hamster ovary (CHO) cell line and characterized its binding and biological characteristics. Despite 25 differences in amino acid sequence from the rat receptor, including a seven-amino acid insertion in the third intracellular loop, mouse and rat receptors were functionally indistinguishable when expressed in CHO cells. Of note, in the mouse pancreatic cell environment, a stable analog of guanosine triphosphate significantly inhibited binding of CCK-OPE, whereas it had no effect on binding to the same receptor on the CHO-CCKM cell line or to the rat receptor in either environment of the acinar cell. This likely reflects a difference in coupling of the mouse receptor to its G protein in the natural environment of the acinar cell. This may relate to differences extrinsic to the receptor, in the stoichiometry or character of G proteins or in the composition or organization of the lipid environment of the mouse acinar cell membrane. Although this may require complementation of the unique sequence of the mouse receptor, that structure alone is insufficient to explain this phenomenon. Receptor microenvironment makes an important, yet often ignored, contribution to receptor function.

Footnotes

  • Send reprint requests to: Laurence J. Miller, M.D., Center for Basic Research in Digestive Diseases, Guggenheim 17, Mayo Clinic, Rochester, MN 55905.

  • ↵1 This work was supported by grants from the National Institutes of Health (DK32878) and the Fiterman Foundation.

  • Abbreviations:
    CCK
    cholecystokinin
    CHO
    Chinese hamster ovary
    CCK-OPE
    Tyr-Gly-[(Nle28,31)CCK26–32]phenethyl ester
    CHO-CCKR
    rat cholecystokinin receptor-bearing Chinese hamster ovary cell line
    GTP
    guanosine triphosphate
    Gpp(NH)p
    5′-guanylylimido diphosphate
    • Received January 31, 1997.
    • Accepted May 21, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherGASTROINTESTINAL PHARMACOLOGY

Differences in Partial Agonist Action at Cholecystokinin Receptors of Mouse and Rat Are Dependent on Parameters Extrinsic to Receptor Structure: Molecular Cloning, Expression and Functional Characterization of the Mouse Type A Cholecystokinin Receptor

D. Ghanekar, E. M. Hadac, E. L. Holicky and L. J. Miller
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1206-1212;

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OtherGASTROINTESTINAL PHARMACOLOGY

Differences in Partial Agonist Action at Cholecystokinin Receptors of Mouse and Rat Are Dependent on Parameters Extrinsic to Receptor Structure: Molecular Cloning, Expression and Functional Characterization of the Mouse Type A Cholecystokinin Receptor

D. Ghanekar, E. M. Hadac, E. L. Holicky and L. J. Miller
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1206-1212;
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