Regulation of Gastrin, Somatostatin and Bombesin Release from the Isolated Rat Stomach by Exogenous and Endogenous Gamma-Aminobutyric Acid

Abstract

Background/Aims and Methods: γ-Aminobutyric acid (GABA) is localized in epithelial cells and intrinsic nerve fibers of the gastric mucosa raising the possibility of a regulatory role for this transmitter. Therefore, it was the aim of the present study to examine the effect of exogenous and endogenous GABA on the neuroendocrine functions of the isolated perfused rat stomach. Results: Infusion of GABA (10^–8, 10^–6, 10^–4 M) caused a significant increase in gastrin release by 187 ± 98, 328 ± 43 and 493 ± 84 pg/20 min and a significant decrease in somatostatin secretion by –540 ± 203, –867 ± 96 and –893 ± 195 pg/20 min, respectively. Release of bombesin-like immunoreactivity (BLI) remained unchanged during infusion of GABA at the concentrations employed. The gastrin and somatostatin responses to 10^–4 M GABA were completely inhibited by the GABA_A antagonist bicuculline (10^–5 M) and the cholinergic blocker atropine (10^–7 M), whereas the GABA_B antagonist CGP 35348 (5 × 10^–5 M) was ineffective. To evaluate the contribution of endogenous GABA in the vagal regulation of gastric neuroendocrine functions, gastrin, somatostatin and BLI responses to electrical stimulation of the vagal nerves were examined in the presence of bicuculline. Vagal stimulation (10 V, 10 Hz, 1 ms) induced a significant inhibition of somatostatin release by –518 ± 78 pg/10 min, which was attenuated to –259 ± 143 pg/10 min (p < 0.05) in the presence of bicuculline. Atropine (10^–7 M) turned vagally induced inhibition of somatostatin release into a stimulation by 928 ± 266 pg/10 min which was not altered by additionally infused bicuculline. Vagally stimulated gastrin release was reduced from 397 ± 47 to 217 ± 72 pg/10 min (p < 0.05) by bicuculline, while atropine had no effect. Vagally induced BLI release was not altered by bicuculline and atropine. Since the effect of bicuculline on vagally induced gastrin release was independent of cholinergic mechanisms, a potential direct effect of GABA on gastrin release was examined in isolated rabbit antral G cells. In this preparation carbachol (10^–4 M) and neuromedin C (10^–9 M) significantly stimulated gastrin release from 2.6 ± 0.4 to 4.9 ± 0.3 and 8.5 ± 0.9% of the total cellular content, respectively, while GABA (10^–10–10^–3 M) changed neither basal nor carbachol- and neuromedin C-stimulated gastrin release. Conclusion: The present data confirm that exogenous GABA stimulates gastrin release and inhibits somatostatin release from the isolated rat stomach via GABA_A receptors by activating cholinergic neurotransmission. Furthermore, it was shown for the first time that endogenous GABA contributes to the vagal regulation of gastrin and somatostatin release from the rat stomach. Inhibition of somatostatin secretion by endogenous GABA is mediated by cholinergic mechanisms, whereas stimulation of gastrin release is mediated by pathways unrelated to the chol...

Regulation of pancreatic islet cell survival and replication by γ-aminobutyric acid

“…Furthermore, given that physiologically relevant concentrations of GABA are present in the circulation, the question of systemic GABA actions arises, as well as the possibility that GABA, like insulin, activates trophic programmes in other organs. This premise is supported by findings that GABA is secreted from vesicles in a calcium-regulated manner [23,43,44], circulates in the blood stream at physiological concentrations [20,41,43] and activates effector systems through GABA receptors (both GABA A and GABA B) on many peripheral tissues [37,39,43,[45][46][47][48][49][50]. Avenues of GABA-related study appear to be plentiful and augur well for the possibility that additional comprehensive treatments for diseases like diabetes remain accessible.…”

“…However, an alternative interpretation of those results is that islets develop normally because GABA is present in the maternal circulation at concentrations of 0.580 to 4 μmol/l [20,41], near the EC 50 value for GABA B receptor activation [34]. Therefore, maternally derived levels of GABA could suffice to activate fetal GABA receptors, preventing any deficiencies that might otherwise result.…”

ECL‐cell histamine mobilization in conscious rats: effects of locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators

“…Surprisingly, GABA was found to raise the microdialysate hisamine concentration by 60% (integrated response). Previously, GABA has been shown to inhibit somatostatin release (Koop & Arnold, 1986; Weigert et al ., 1998), while having no effect on isolated ECL cells (Lindström et al ., 1997). Hence, the weak stimulatory effect of GABA on ECL‐cell histamine mobilization is likely to be indirect.…”

GABA C receptors in neuroendocrine gut cells: a new GABA-binding site in the gut

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