Interaction of the Growth Hormone-Releasing Peptides Ghrelin and Growth Hormone-Releasing Peptide-6 with the Motilin Receptor in the Rabbit Gastric Antrum

Abstract

The structural relationship between the motilin and the growth hormone secretagogue receptor (GHS-R), and between their respective ligands, motilin and ghrelin, prompted us to investigate whether ghrelin and the GHS-R agonist growth hormonereleasing peptide-6 (GHRP-6), could interact with the motilin receptor. The interaction was evaluated in the rabbit gastric antrum with binding studies on membrane preparations and with contraction studies on muscle strips in the presence of selective antagonists under conditions of electrical field stimulation (EFS) or not. Binding studies indicated that the affinity (pK d ) for the motilin receptor was in the order of ghrelin (4.23 Ϯ 0.07) Ͻ GHRP-6 (5.54 Ϯ 0.08) Ͻ motilin (9.13 Ϯ 0.03). The interaction of ghrelin with the motilin receptor requires the octanoyl group. Motilin induced smooth muscle contractile responses but ghrelin and GHRP-6 were ineffective. EFS elicited on-and off-responses that were increased by motilin already at 10 Ϫ9 M, but not by 10 Ϫ5 M ghrelin. In contrast, GHRP-6 also enhanced the on-and off-responses. The motilin antagonist Phe-cyclo[Lys-Tyr(3-tBu)-␤Ala-] trifluoroacetate (GM-109) blocked the effect of GHRP-6 on the off-responses but not on the on-responses. Under nonadrenergic noncholinergic conditions, the effects of motilin and GHRP-6 on the on-responses were abolished; those on the off-responses were preserved. All responses were blocked by neurokinin (NK) 1 and NK 2 antagonists. In conclusion, ghrelin is unable to induce contractions via the motilin receptor. However, GHRP-6 enhances neural contractile responses, partially via interaction with the motilin receptor on noncholinergic nerves with tachykinins as mediator, and partially via another receptor that may be a GHS-R subtype on cholinergic nerves that corelease tachykinins.

Energy Homeostasis and Gastric Emptying in Ghrelin Knockout Mice

“…This suggests that the effects on food intake and gastric emptying are mediated via different pathways. Previous studies have shown that the starvation signal and the effect on motility by ghrelin are relayed to the brain via vagal afferents (Masuda et al, 2000;Date et al, 2002;Fujino et al, 2003), whereas the effect on motility may also depend upon activation of peripheral receptors (Depoortere et al, 2003Kitazawa et al, 2005;Xu et al, 2005). Selective up-and/or down-regulation of central and peripheral receptors may determine the final effect of exogenous ghrelin on food intake and gastric emptying.…”

Physiological characteristics of gastric contractions and circadian gastric motility in the free-moving conscious house musk shrew (Suncus murinus)

“…However, in rodents, although specific phase III-like contractions were observed every 15 min in the fasted state (7,48), many reports claimed that administration of motilin or a motilin agonist failed to stimulate contraction of rat intestinal muscle strips and gastric emptying. For example, Depoortere et al (4,5) found that motilin did not accelerate rat gastric emptying and transit, and they suggested that motilin and its receptor do not exist or are nonfunctional in these species. Moreover, although several research groups, including our group, have tried to determine the sequence of rat motilin and motilin receptor, no convincing results have been reported so far (1,13), and Peeters (34) described rats and mice as natural motilin and motilin receptor knockouts.…”

Enhanced Gastrointestinal Motility with Orally Active Ghrelin Receptor Agonists

“…Ghrelin stimulates the migrating motor complex, resulting in increased gastric emptying and upper GI tract motility in a variety of species (Fujino et al, 2003;Tack et al, 2006;Wang et al, 2007). Despite 50% structural homology between ghrelin and the prokinetic peptide hormone motilin, the activity of these two hormones has been shown convincingly to function via distinct receptors (Depoortere et al, 2003;Sanger, 2008). The ability to stimulate hunger, FI, and GI motility suggests that ghrelin agonists may represent an attractive and unique therapeutic strategy for the treatment of motility disorders (Sanger and Alpers, 2008), such as diabetic and idiopathic gastroparesis, postoperative ileus, opiate-induced bowel dysfunction, and chronic constipation of idiopathic origin (Murray et al, 2005;Tack et al, 2005;Levin et al, 2006;Qiu et al, 2008b,c).…”