A relationship between motilin and growth hormone secretagogue receptors.
by endocrine cells in the oxyntic mucosa of the stomach as an endogenous ligand for the growth hormone (GH) secretagogue receptor [1–4]. The motilin receptor is 52% identical to the human growth hormone on the relationship between the structure of motilin, the natural peptide ligand, .. of the motilin receptor with the growth hormone secretagogue receptors. A relationship between motilin and growth hormone secretagogue receptors. Nunoi H(1), Matsuura B, Utsunomiya S, Ueda T, Miyake T.
International Journal of Peptides
Together, these represent a new Class I receptor family. Our aim in the present work is to gain insight into the molecular basis of binding of motilin to its receptor using photoaffinity labeling.
These were demonstrated to represent fragments that included both the first and the large second extracellular loop domains, with the latter representing a unique structural feature of this receptor. The spatial approximation of the pharmacophoric domain of motilin with these receptor domains support their functional importance as well. Motilin has long been recognized as an important endogenous peptide regulator of gastrointestinal motor function 12.
Growth hormone secretagogue receptor
The receptor for this hormone has also been demonstrated to represent a clinically useful pharmacological target, activated by erythromycin 34. While there have been extensive physiological and pharmacological studies of motilin action, including extensive analysis of peptide structure-activity relationshipsthe motilin receptor MtlR 1 has been difficult to isolate and biochemically characterize.
Using a unique high throughput screen of compounds that can interact with cloned orphan receptors, the cDNA encoding the human motilin receptor originally isolated as orphan clone GPR38 was finally identified in 8. Sequence analysis demonstrated that this represents a member of a new subgroup within the Class I family of G protein-coupled receptors that is defined by structural homology with a series of growth hormone secretagogue receptors 9 Because this group of receptors has only been recognized for a short time, no specific receptor domains of importance for binding or activation have yet been identified.
Better understanding of the molecular basis of activation of this receptor by its natural ligand may provide important insights for drug development. Many existing structure-activity studies have focused on the relationship between the structure of motilin, the natural peptide ligand, and its ability to bind to or to stimulate contractile activity of natural motilin receptor-bearing gastrointestinal smooth muscle tissue11 These studies have demonstrated that the amino-terminal portion of motilin, including residues 1—9, is devoid of any activity, while extension of this domain beyond the first nine residues restores binding and biological activity 68.
Such observations have established that the pharmacophoric domain of this hormone represents its amino-terminal decapeptide.
In this work, we have attempted to develop the tools necessary to begin to gain an understanding of the molecular basis of motilin binding to its receptor. This included the establishment of a cell line that expresses a high density of functional motilin receptors and the development of a radioiodinatable motilin analogue that incorporates a photolabile residue within this critical pharmacophoric domain of the natural peptide ligand.
To date, encouraging results of the gastrokinetic capacity of ghrelin in dogs are few. Effects of canine ghrelin on gastric emptying in conscious dogs. Saline and canine ghrelin were administered intravenously. In humans, Binn et al. These observations suggest the potential for ghrelin as a prokinetic. TZP, a synthetic ghrelin-receptor agonist, has been shown to be an active gastrokinetic agent in rats [ 62 ] and has already been tested in humans [ 63 ].
However, it seems difficult to believe that plasma ghrelin could play a physiological role in these digestive physiological events. Most evidence indicates that ghrelin plasma levels are high during the fasting period and decrease after meal ingestion.
Growth hormone secretagogue receptor - Wikipedia
Most GI peptides increase after a meal. Motilin and ghrelin are the only hormones known to decrease in the postprandial period [ 64 ]. The observed biological action of the peptide, stimulation of meal gastric emptying, appears to be in contradiction with its endogenous release being suppressed after eating.
Conclusion Ghrelin is of great interest, as is motilin, to the GI physiologist. The value of ghrelin as a prokinetic agent may soon be revealed. However, the physiological roles of ghrelin, especially in dogs and humans, need to be clarified.