Lack of cholinergic innervation in gastric mucosa does not affect gastrin secretion or basal acid output in neurturin receptor GFRα2 deficient mice

Key points • Nervous control over gastric function is mediated via intrinsic neurons in the gastric myenteric ganglia. The majority of these neurons are cholinergic and are innervated by preganglionic efferents from the vagus nerve. Intact vagal innervation is crucial for gastric acid secretion and mucosal maintenance since vagotomy is known to abolish both basal and stimulated acid secretion and unilateral vagotomy causes gastric mucosal atrophy. • Neurturin, a neurotrophic factor signalling via GDNF-family receptor α2 (GFRα2) is an important factor for parasympathetic innervation of many target tissues, but its role in gastric innervation is unknown. • GFRα2-deficient (KO) mice lack virtually all cholinergic nerve fibres and associated glial cells in the gastric mucosa, yet have normal gastric morphology, gastrin secretion, and basal and maximal histamine-stimulated acid secretion. • Blocking of myenteric ganglia with hexamethonium severely decreased basal acid secretion in wild-type mice but had no effect on the GFRα2-KO animals. Carbachol-stimulated acid secretion was higher in GFRα2-KO mice. Blocking of muscarinic receptors with atropine inhibited basal acid secretion in both genotypes suggesting that constitutive activity of muscarinic receptors may facilitate basal acid secretion. Abstract  Efferent signals from the vagus nerve are thought to mediate both basal and meal-induced gastric acid secretion, and provide trophic support of the mucosa. However, the underlying mechanisms are incompletely understood. Neurturin, signalling via glial cell line-derived neurotrophic factor (GDNF)-family receptor α2 (GFRα2), is essential for parasympathetic innervation of many target tissues but its role in gastric innervation is unknown. Here we show that most nerve fibres in wild-type mouse gastric mucosa, including all positive for gastrin-releasing peptide, are cholinergic. GFRα2-deficient (KO) mice lacked virtually all cholinergic nerve fibres and associated glial cells in the gastric (oxyntic and pyloric) mucosa but not in the smooth muscle, consistent with the selective expression of neurturin mRNA in the gastric mucosa. 2-Deoxyglucose and hexamethonium failed to affect acid secretion in the GFRα2-KO mice indicating the lack of functional innervation in gastric mucosa. Interestingly, basal and maximal histamine-induced acid secretion did not differ between wild-type and GFRα2-KO mice. Moreover, circulating gastrin levels in both fasted and fed animals, thickness of gastric mucosa, and density of parietal and different endocrine cells were similar. Carbachol-stimulated acid secretion was higher in GFRα2-KO mice, while atropine reduced basal secretion similarly in both genotypes. We conclude that cholinergic innervation of gastric mucosa depends on neurturin-GFRα2 signalling but is dispensable for gastrin secretion and for basal and maximal acid output. Basal acid secretion in the KO mice appears to be, at least partly, facilitated by constitutive activity of muscarinic receptors.