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Department of Biochemistry, Molecular Biology and Cell Biology Northwestern University Evanston, Illinois 60208
The hypothalamic peptide GH-releasing hormone
(GHRH) stimulates the release of GH from the pituitary through binding
and activation of the GHRH receptor, which belongs to the family of G
protein-coupled receptors. The objective of this study was to identify
regions of the receptor critical for interaction with the ligand by
expressing and analyzing truncated and chimeric epitope-tagged GHRH
receptors. Two truncated receptors, GHRH
N, in which part of the
N-terminal domain between the putative signal sequence and the first
transmembrane domain was deleted, and GHRHC, which was truncated
downstream of the first intracellular loop, were generated. Both the
receptors were deficient in ligand binding, indicating that neither the
N-terminal extracellular domain (N terminus) nor the membrane-spanning
domains with the associated extracellular loops (C terminus) are alone
sufficient for interaction with GHRH. In subsequent studies, chimeric
proteins between the receptors for GHRH and vasoactive intestinal
peptide (VIP) or secretin were generated, using the predicted start of
the first transmembrane domain as the junction for the exchange of the
N terminus between receptors. The chimeras having the N terminus of the
GHRH receptor and the C terminus of either the VIP or secretin receptor
(GNVC and
GNSC) did not bind GHRH
or activate adenylate cyclase after GHRH treatment. The reciprocal
chimeras having the N terminus of either the VIP or secretin receptors
and the C terminus of the GHRH receptor
(VNGC and
SNGC) bound GHRH and
stimulated cAMP accumulation after GHRH treatment. These results
suggest that although the N-terminal extracellular domain is essential
for ligand binding, the transmembrane domains and associated
extracellular loop regions of the GHRH receptor provide critical
information necessary for specific interaction with GHRH.
(Molecular Endocrinology 12: 750–765, 1998)
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