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.
© 2019 The British Pharmacological Society.
Conflict of interest statement
The authors declare no conflicts of interest.
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Evidence for Metabotropic Function of Epithelial Nicotinic Cholinergic Receptors in Rat ColonL Lottig et al. Br J Pharmacol 176 (9), 1328-1340. PMID 30807644.These results suggest that epithelial nAChR activate the Na+ -K+ -pump via a PKC dependent on a sufficient cytosolic Ca2+ concentration. …