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J Biol Chem, Vol. 274, Issue 35, 24593-24601, August 27, 1999

Characterization of the Carboxyl-terminal Domain of the Rat Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor
A ROLE FOR SERINES 426 AND 427 IN REGULATING THE RATE OF INTERNALIZATION

Michael B. Wheeler, Richard W. Gelling^§, Simon A. Hinke^§, Ba Tu, Raymond A. Pederson^§, Francis Lynn^§, Jan Ehses^§, and Christopher H. S. McIntosh^§

From the  Departments of Medicine and Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada and the ^§ Department of Physiology, University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada

Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone involved in the regulation of insulin secretion. In non-insulin-dependent diabetes mellitus insulin responses to GIP are blunted, possibly due to altered signal transduction or reduced receptor number. Site-directed mutagenesis was used to construct truncated GIP receptors to study the importance of the carboxyl-terminal tail (CT) in binding, signaling, and receptor internalization. Receptors truncated at amino acids 425, 418, and 405, expressed in COS-7 or CHO-K1 cells, exhibited similar binding to wild type receptors. GIP-dependent cAMP production with the 405 mutant was decreased in COS-7 cells. Maximal cAMP production in CHO-K1 cells was reduced with all truncated forms. Binding was undetectable with a receptor truncated at amino acid 400; increasing tail length by adding 5 alanines restored binding and signaling. Mutants produced by alanine scanning of residues 394-401, adjacent to transmembrane domain 7, were all functional. CT truncation by 30 or more amino acids, mutation of serines 426/427, singly or combined, or complete CT serine knockout all reduced receptor internalization rate. The majority of the GIP receptor CT is therefore not required for signaling, a minimum chain length of ~405 amino acids is needed for receptor expression, and serines 426 and 427 are important for regulating rate of receptor internalization.

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