Heterodimerization of Type A and B Cholecystokinin Receptors Enhance Signaling and Promote Cell Growth

Zhi Jie Cheng, Kaleeckal G. Harikumar, Eileen L. Holicky, Laurence J. Miller

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Dimerization of several G protein-coupled receptors has recently been described, but little is known about its clinical and functional relevance. Cholecystokinin (CCK) and gastrin are structurally related gastrointestinal and neuronal peptides whose functions are mediated by two structurally related receptors in this superfamily, the type A and B CCK receptors. We previously demonstrated spontaneous homodimerization of type A CCK receptors and the dissociation of those complexes by agonist occupation (Cheng, Z. J., and Miller, L. J. (2001) J. Biol. Chem. 276, 48040-48047). Here, for the first time, we also demonstrate spontaneous homodimerization of type B CCK receptors, as well as heterodimerization of that receptor with the type A CCK receptor. Unlike type A CCK receptor dimers, the homodimerization of type B CCK receptors was not affected by ligand occupation. However, although heterodimers of type A and B CCK receptors bound natural agonists normally, they exhibited unusual functional and regulatory characteristics. Such complexes demonstrated enhanced agonist-stimulated cellular signaling and delayed agonist-induced receptor internalization. As a likely consequence, agonist-stimulated cell growth was markedly enhanced in cells simultaneously expressing both of these receptors. Our results provide the first evidence that heterodimerization of G protein-coupled receptors can form a more "powerful" signaling unit, which has potential clinical significance in promoting cell growth.

Original languageEnglish (US)
Pages (from-to)52972-52979
Number of pages8
JournalJournal of Biological Chemistry
Issue number52
StatePublished - Dec 26 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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