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Submucosal enteric neurons of the cavine distal colon are sensitive to hypoosmolar stimuli.

ABSTRACT:

Key points

Neurons of the enteric submucous plexus are challenged by osmolar fluctuations during digestion and absorption of nutrients. Central neurons are very sensitive to changes in osmolality but knowledge on that issue related to enteric neurons is sparse. The present study focuses on investigation of osmosensitivity of submucosal neurons including potential molecular mediating mechanisms. Results show that submucosal neurons respond to hypoosmolar stimuli with increased activity which is partially mediated by the transient receptor potential vanilloid 4 channel. We provided important information on osmosensitive properties of enteric neurons. These data are fundamental to better explain the nerve-mediated control of the gastrointestinal functions during physiological and pathophysiological (diarrhoea) conditions.

Abstract

Enteric neurons are located inside the gut wall, where they are confronted with changes in osmolality during (inter-) digestive periods. In particular, neurons of the submucous plexus (SMP), located between epithelial cells and blood vessels may sense and respond to osmotic shifts. The present study was conducted to investigate osmosensitivity of enteric submucosal neurons and the potential role of the transient receptor potential vanilloid 4 channel (TRPV4) as a mediator of enteric neuronal osmosensitivity. Therefore, freshly dissected submucosal preparations from guinea pig colon were investigated for osmosensitivity using voltage-sensitive dye and Ca²⁺ imaging. Acute hypoosmolar stimuli (final osmolality reached at ganglia of 94, 144 and 194 mOsm kg^-1 ) were applied to single ganglia using a local perfusion system. Expression of TRPV4 in the SMP was quantified using qRT-PCR, and GSK1016790A and HC-067047 were used to activate or block the receptor, respectively, revealing its relevance in enteric osmosensitivity. On average, 11.0 [7.0/17.0] % of submucosal neurons per ganglion responded to the hypoosmolar stimulus. The Ca²⁺ imaging experiments showed that glia responded to the hypoosmolar stimulus, but with a delay in comparison with neurons. mRNA expression of TRPV4 could be shown in the SMP and blockade of the receptor by HC-067047 significantly decreased the number of responding neurons (0.0 [0.0/6.3] %) while the TRPV4 agonist GSK1016790A caused action potential discharge in a subpopulation of osmosensitive enteric neurons. The results of the present study provide insight into the osmosensitivity of submucosal enteric neurons and strongly indicate the involvement of TRPV4 as an osmotransducer.

SUBMITTER: Kollmann P

PROVIDER: S-EPMC7722197 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background and purposeAdenosine A(3) receptors mediate beneficial effects in experimental colitis, but their involvement in enteric neuromuscular functions during bowel inflammation is undetermined. This study investigated the regulatory role of A(3) receptors on colonic motility in the presence of experimental colitis.Experimental approachColitis was induced in rats by 2,4-dinitrobenzenesulfonic acid. A(3) receptors and adenosine deaminase (ADA, adenosine catabolic enzyme) mRNA were examined by RT-PCR. Tissue distribution of A(3) receptors was detected by confocal immunofluorescence. The effects of 2,3-ethyl-4,5-dipropyl-6-phenylpyridine-3-thiocarboxylate-5-carboxylate (MRS1523) (MRS, A(3) receptor antagonist), 2-chloro-N(6) -(3-iodobenzyl)-adenosine-5'-N-methyluronamide (2Cl-IB-MECA) (CIB, A(3) receptor agonist), dipyridamole (DIP, adenosine transport inhibitor) and ADA were assayed on contractile responses evoked by electrical stimulation (ES) or carbachol in colonic longitudinal muscle preparations (LMP).Key resultsRT-PCR showed A(3) receptors and ADA mRNA in normal colon and their increased level in inflamed tissues. Immunofluorescence showed a predominant distribution of A(3) receptors in normal myenteric ganglia and an increased density during colitis. MRS enhanced ES-induced cholinergic contractions in normal LMP, but was less effective in inflamed tissues. After pretreatment with dipyridamole plus ADA, to reduce extracellular adenosine, CIB decreased cholinergic motor responses of normal LMP to ES, with enhanced efficacy in inflamed LMP. A(3) receptor ligands did not affect carbachol-induced contractions in LMP from normal or inflamed colon.Conclusions and implicationsNormally, adenosine modulated colonic cholinergic motility via activation of A(3) receptors in the myenteric plexus. A(3) receptor-mediated tonic inhibitory control by adenosine was impaired in inflamed bowel, despite increased density of functioning and pharmacologically recruitable A(3) receptors.

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Submucosal enteric neurons of the cavine distal colon are sensitive to hypoosmolar stimuli.

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