Different receptors mediate the action of bombesin-related peptides on gastric smooth muscle cells

Abstract

Recent studies suggest that different subtypes of receptors may mediate the action of various bombesin-related peptides in different tissues. In the present study the ability of bombesin and its structurally related peptides [litorin, gastrin-releasing peptide (GRP), GRP18-27, neuromedin B, [Leu8]litorin, and bombesin nonapeptide BN(6-14)] to interact with smooth muscle cells isolated from guinea pig stomach was investigated. Each peptide induced a specific contractile response with potencies (D50 in pM) of [Leu8]litorin (0.7) greater than bombesin (1.2) greater than litorin (3) greater than neuromedin B (3.5) = GRP (3.8) = GRP18-27 (3.9) greater than BN(6-14) (70.9). The specific bombesin receptor antagonist psi 13,14-bombesin differed in its potency for inhibiting equipotent concentrations of bombesin, GRP, or neuromedin B, was equipotent for bombesin or GRP (IC50 12.7 and 22.1 nM), and was 11 times less potent for neuromedin B (IC50 234.5 nM), suggesting the presence of subtypes of receptors mediating the action of bombesin-related peptides. To further investigate this possibility, a technique of receptor protection that enables selective preservation of one receptor type was used. GRP or bombesin protected completely the response to GRP or bombesin but abolished the subsequent contractile response to neuromedin B. Neuromedin B, instead, protected only the response to neuromedin B. These results demonstrate that gastric smooth muscle cells possess specific receptors that interact with bombesin-related peptides and that two receptor subtypes mediate the contractile response to these peptides: one subtype is selective for bombesin or GRP, the other for neuromedin B.

Gastrin-releasing peptide is a modulatory neurotransmitter of the descending phase of the peristaltic reflex

“…Because these neurons release VIP, PACAP, and NO as motor transmitters to cause relaxation of circular muscle, it is unlikely that GRP acts as motor transmitter in these neurons, although it is possible that GRP could act a neuromodulator regulating the release of these other motor transmitters by a presynaptic action. Numerous studies demonstrate that GRP causes direct contraction of smooth muscle cells and muscle strips derived from the circular muscle layer (5,7,20,22,29,39). In the three-compartment preparation of rat colon used in the present study, addition of exogenous GRP to either the orad or caudad peripheral compartment caused contraction, sometimes followed by increased spontaneous activity (unpublished observations).…”

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

“…Numerous classes of selective BB 2 receptor antagonists were developed before the cloning of the BB 1 , and these also confirmed the presence of the BB 1 on esophageal smooth muscle (von Schrenck et al, 1990). After the pharmacologic description of BB 1 on esophageal muscle and before its cloning in 1991, by use of selective BB 2 receptor antagonists or binding studies with radiolabeled NMB and selective agonists or BB 2 receptor antagonists, BB 1 receptors were demonstrated in the CNS (Ladenheim et al, 1990) and on gastric smooth muscle cells (Severi et al, 1991).…”

“…Early studies on the biologic effects of the different bombesin peptides isolated from frog skins, primarily examining their effects on contraction of isolated smooth muscle preparations from various tissues, demonstrated markedly varying potencies, which suggested that more than one subtype of bombesin receptor might exist (Falconieri Erspamer et al, 1988;Regoli et al, 1988;Severi et al, 1991). Binding studies and the development of highly selective antagonists established unequivocally the existence of two different classes of receptors in mammalian tissues mediating the actions of these peptides (Jensen et al, 1978;Moody et al, 1978;Jensen and Gardner, 1981;Coy et al, 1988;von Schrenck et al, 1989von Schrenck et al, , 1990Ladenheim et al, 1990;Jensen and Coy, 1991;Metz et al, 1992).…”

Constitutive activation of the gastrin-releasing peptide receptor expressed by the nonmalignant human colon epithelial cell line NCM460.

“…GRP binds to and activates a specific receptor which is a member of the seven transmembrane-spanning, G protein-coupled receptor superfamily (1)(2)(3). In the GI tract, GRP receptors (GRP-R) are expressed by the myenteric and submucosal neural plexuses innervating the underlying smooth muscle, where they act to modulate intestinal contractility and transit (4,5). In mice (6), pigs (7,8), rats, guinea pigs, and chickens (9,10), GRP-R also are expressed by mucosal epithelial cells lining the GI tract.…”