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Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon.

ABSTRACT: BACKGROUND AND PURPOSE:ACh exerts its actions via nicotinic (nAChR) and muscarinic receptors. In the peripheral nervous system, ionotropic nAChR mediate responses in excitable cells. However, recent studies demonstrate the expression of nAChR in the colonic epithelium, which are coupled to an induction of Cl- secretion via activation of the Na+ -K+ -pump. EXPERIMENTAL APPROACH:In order to find out whether these epithelial nAChR function as ionotropic receptors, intracellular microelectrode and imaging experiments were performed in isolated crypts from rat colon. Apically permeabilized epithelia were used to measure pump current across the basolateral membrane. KEY RESULTS:Imaging experiments with the Na+ -sensitive dye SBFI revealed that nicotine induced a decrease in the cytosolic Na+ concentration concomitant with a fall in the cytosolic Ca2+ concentration in about 50% of the cells. as shown in fura-2 experiments. Nicotine hyperpolarized the membrane by 6.4 ± 2.1 mV. These observations contradict the assumption that epithelial nAChR function as ligand-gated non-selective cation channels. The decrease in the cytosolic Na+ concentration was strongly delayed, when the Na+ -K+ -pump was inhibited by scilliroside. Ussing chamber experiments revealed a strong dependence of the nicotine-induced pump current on the presence of Ca2+ , and chelation of cytosolic Ca2+ with BAPTA prevented the fall in the cytosolic Na+ concentration in SBFI-loaded crypts. Inhibition of PKC with GF 109203X or Goe 6983 significantly reduced the nicotine-induced pump current. CONCLUSIONS AND IMPLICATIONS:These results suggest that epithelial nAChR activate the Na+ -K+ -pump via a PKC dependent on a sufficient cytosolic Ca2+ concentration.

SUBMITTER: Lottig L

PROVIDER: S-EPMC6468263 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon.

Lottig Lena L Bader Sandra S Jimenez Marcel M Diener Martin M

British journal of pharmacology 20190409 9

<h4>Background and purpose</h4>ACh exerts its actions via nicotinic (nAChR) and muscarinic receptors. In the peripheral nervous system, ionotropic nAChR mediate responses in excitable cells. However, recent studies demonstrate the expression of nAChR in the colonic epithelium, which are coupled to an induction of Cl<sup>-</sup> secretion via activation of the Na<sup>+</sup> -K<sup>+</sup> -pump.<h4>Experimental approach</h4>In order to find out whether these epithelial nAChR function as ionotrop ...[more]

PMID: 30807644

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Project description:Respiratory distress syndrome is responsible for 40 to 60 percent mortality. An over mortality of about 10 percent could result from additional lung injury and inflammation due to the life-support mechanical ventilation, which stretches the lung. It has been recently demonstrated, in vitro, that pharmacological activation of the alpha 7 nicotinic receptors (α7-nAChR) could down regulate intracellular mediators involved in lung cell inflammatory response to stretch. Our aim was to test in vivo the protective effect of the pharmacological activation of the α7-nAChR against ventilator-induced lung injury (VILI). Anesthetized rats were ventilated for two hours with a high stretch ventilation mode delivering a stroke volume large enough to generate 25-cmH(2)O airway pressure, and randomly assigned to four groups: pretreated with parenteral injection of saline or specific agonist of the α7-nAChR (PNU-282987), or submitted to bilateral vagus nerve electrostimulation while pre-treated or not with the α7-nAChR antagonist methyllycaconitine (MLA). Controls ventilated with a conventional stroke volume of 10 mL/kg gave reference data. Physiological indices (compliance of the respiratory system, lung weight, blood oxygenation, arterial blood pressure) and lung contents of inflammatory mediators (IL-6 measured by ELISA, substance P assessed using HPLC) were severely impaired after two hours of high stretch ventilation (sham group). Vagal stimulation was able to maintain the respiratory parameters close to those obtained in Controls and reduced lung inflammation except when associated to nicotinic receptor blockade (MLA), suggesting the involvement of α7-nAChR in vagally-mediated protection against VILI. Pharmacological pre-treatment with PNU-282987 strongly decreased lung injury and lung IL-6 and substance P contents, and nearly abolished the increase in plasmatic IL-6 levels. Pathological examination of the lungs confirmed the physiological differences observed between the groups. In conclusion, these data suggest that the stimulation of α7-nAChR is able to attenuate VILI in rats.

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Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon.

Publications

Evidence for metabotropic function of epithelial nicotinic cholinergic receptors in rat colon.

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