![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
MH Holtmann, EM Hadac, CD Ulrich and LJ Miller
Center for Basic Research in Digestive Diseases, Mayo Clinic and Foundation, Rochester, Minnesota, USA.
The affinity and specificity of the binding interaction between ligands and their receptors are key for appropriate hormonal regulation of target tissues. However, it is now apparent that vasoactive intestinal polypeptide (VIP) binds to the rat secretin receptor with similar affinity to that for its natural ligand, secretin (Holtmann et al., 1995). In this report, we establish that this is not a characteristic of the human secretin receptor, and use rat-human secretin receptor chimeras, site mutants and truncated receptor constructs to establish the molecular basis for this unusual binding interaction. Of note, isolated N-terminal domains of the rat secretin and the VIP receptors are capable of high affinity binding of VIP. In the recently recognized secretin family of receptors, this domain has six conserved cysteine residues and disulfide bonds that are likely important to achieve the complex conformation critical for this binding. A single acidic residue (Asp98) present in the rat secretin receptor appears to be critical, because a site-mutant changing this to the polar, but uncharged residue present in that position in the human receptor (Asn) eliminates the high affinity binding of VIP. Of interest, a previously identified critical basic residue in VIP (Lys15) provides a candidate for charge- pairing with this residue, potentially aligning the peptide ligand in a nonproductive orientation within this receptor.
This article has been cited by other articles:
|
|
 |
|
  I. Nishijima, T. Yamagata, C. M. Spencer, E. J. Weeber, O. Alekseyenko, J. D. Sweatt, M. Y. Momoi, M. Ito, D. L. Armstrong, D. L. Nelson, et al. Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behavior Hum. Mol. Genet., November 1, 2006; 15(21): 3241 - 3250. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. G. Harikumar, K. Hosohata, D. I. Pinon, and L. J. Miller Use of Probes with Fluorescence Indicator Distributed throughout the Pharmacophore to Examine the Peptide Agonist-binding Environment of the Family B G Protein-coupled Secretin Receptor J. Biol. Chem., February 3, 2006; 281(5): 2543 - 2550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. H. Carter, M. Shimizu, M. D. Luck, and T. J. Gardella The Hydrophobic Residues Phenylalanine 184 and Leucine 187 in the Type-1 Parathyroid Hormone (PTH) Receptor Functionally Interact with the Amino-terminal Portion of PTH-(1-34) J. Biol. Chem., November 5, 1999; 274(45): 31955 - 31960. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Mannstadt, H. Juppner, and T. J. Gardella Receptors for PTH and PTHrP: their biological importance and functional properties Am J Physiol Renal Physiol, November 1, 1999; 277(5): F665 - F675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Luck, P. H. Carter, and T. J. Gardella The (1-14) Fragment of Parathyroid Hormone (PTH) Activates Intact and Amino-Terminally Truncated PTH-1 Receptors Mol. Endocrinol., May 1, 1999; 13(5): 670 - 680. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. D. Ulrich II, P. Wood, E. M. Hadac, E. Kopras, D. C. Whitcomb, and L. J. Miller Cellular distribution of secretin receptor expression in rat pancreas Am J Physiol Gastrointest Liver Physiol, December 1, 1998; 275(6): G1437 - G1444. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
