gastrin-heptadecapeptide--nle(15)- and cholecystokinin-39

In the preceding paper, by means of selective agonists to gastrin (HG-17) and cholecystokinin (CCK-39), we evidenced the existence of "gastrin-type" receptors that could regulate histamine release and "CCK-type" receptors that could stimulate somatostatin release in isolated rabbit fundic non-parietal cells (F1 cells). Furthermore, these receptors could induce phosphoinositide breakdown. To confirm the involvement of these receptor types in these biological and biochemical processes, we used selective antagonists, L-364,718 (3-(benzoylamino)-benzodiazepine) specific to "CCK-A-type" receptor and L-365,260 (3-(acylamino)-benzodiazepine) specific to "gastrin/CCK-B-type" receptor. Neither L-364,718 nor L-365,260 alone caused any significant stimulation of [3H]inositol phosphate ([3H]InsP) production and release of histamine or somatostatin-like immunoreactivity (SLI). Each analogue inhibited in a dose-dependent manner [125I]HG-17 or [125I]CCK-39 binding to F1 cells, [3H]InsP accumulation and histamine and SLI release stimulated by HG-17 or CCK-39. L-365,260 appeared to be 30-70 times more potent than L-364,718 in inhibiting [125I]HG-17 binding to F1 cells, as well as HG-17-induced [3H]InsP accumulation and HG-17-or CCK-39-enhanced histamine release (IC50 values: approximately 5-20 nM for L-365,260 and approximately 200-1500 nM for L-364,718). In contrast, L-364,718 was 200 to 400 times more potent than L-365,260 in inhibiting [125I]CCK-39 binding to F1 cells, CCK-39-induced [3H]-InsP accumulation and SLI release stimulated by CCK-39 or HG-17 (IC50 values: approximately 0.3-1 nM for L-364,718 and 100-200 nM for L-365,260). These results led to conclude: (i) the existence of a "gastrin-type" receptor related to histamine release: (ii) the existence of a "CCK-A-type" receptor related to somatostatin release; (iii) the existence of "gastrin type" and "CCK-A-type" receptors linked to the phosphoinositide breakdown pathway.

Topics: Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Gastric Mucosa; Gastrins; Histamine Release; Inositol Phosphates; Iodine Radioisotopes; Phenylurea Compounds; Rabbits; Receptors, Cholecystokinin; Somatostatin

A previous study has suggested the presence of two distinct binding sites for gasrin and cholecystokinin (CCK) in isolated non-parietal cells from rabbit gastric mucosa: a receptor which binds CCK-8 and CCK-39 with a high affinity and a receptor which binds gastrin and CCK-8 with the same high affinity and CCK-39 with a lower affinity. To characterize these receptors, their ability to induce phosphoinositide breakdown was investigated. Gastrin (HG-17), CCK-39 and CCK-8 induced [3H]-inositol phosphate ([3H]InsP) accumulation from [3H]inositol prelabelled cells with a high potency (EC50: 0.3-2.7 nM) but CCK-8 exhibited a higher efficacy than HG-17 or CCK-39. HG-17, CCK-8 and CCK-39 induced a rapid accumulation of [3H]inositol monophosphate ([3H]InsP1), [3H]inositol bisphosphate ([3H]InsP2) and [3H]inositol trisphosphate ([3H]InsP3) but CCK-8 caused a two times higher accumulation than HG-17 or CCK-39. Histamine- and somatostatin-containing cells appeared to be located in this non-parietal cells population. HG-17, CCK-8 and CCK-39 dose-dependently induced histamine release with the following order of potency: HG-17 = CCK-8 (EC50 approximately 0.2 nM) greater than CCK-39 (EC50 approximately 4 nM). In addition, HG-17 exhibited the highest efficacy. HG-17, CCK-8 and CCK-39 enhanced somatostatin-like immunoreactivity (SLI) release with the following order of potency: CCK-8 (EC50 approximately 0.1 nM) = CCK-39 greater than HG-17 (EC50 approximately 10 nM); CCK-8 and CCK-39 exhibited the highest efficacy. These results led us to the following conclusions: (i) existence of a "gastrin-type" and of a "CCK-type" receptor mediating phosphoinositide breakdown in these gastric non-parietal cells. CCK-8 interacts with both receptor-types with the same affinity; (ii) the release of histamine from histamine-containing cells could be induced following "gastrin-type" receptors activation; (iii) somatostatin release from D-cells present in this non-parietal cells population could be induced following "CCK-type" receptors activation.

Topics: Animals; Cholecystokinin; Gastric Mucosa; Gastrins; Histamine Release; Inositol Phosphates; Rabbits; Receptors, Cholecystokinin; Sincalide; Somatostatin; Tritium