| First Author | Kumar P | Year | 2020 |
| Journal | Br J Pharmacol | Volume | 177 |
| Issue | 24 | Pages | 5595-5608 |
| PubMed ID | 32959891 | Mgi Jnum | J:322921 |
| Mgi Id | MGI:6727742 | Doi | 10.1111/bph.15270 |
| Citation | Kumar P, et al. (2020) Nicotine stimulates ion transport via metabotropic beta4 subunit containing nicotinic ACh receptors. Br J Pharmacol 177(24):5595-5608 |
| abstractText | BACKGROUND AND PURPOSE: Mucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown. EXPERIMENTAL APPROACH: Transepithelial short circuit currents (ISC ) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca(2+) ]i were studied on freshly dissociated mouse tracheal epithelial cells. KEY RESULTS: Apical application of the nAChR agonist nicotine transiently increased ISC . The nicotine effect was abolished by the nAChR antagonist mecamylamine. alpha-Bungarotoxin (alpha7 antagonist) had no effect. The agonists epibatidine (alpha3beta2, alpha4beta2, alpha4beta4 and alpha3beta4) and A-85380 (alpha4beta2 and alpha3beta4) increased ISC . The antagonists dihydro-beta-erythroidine (alpha4beta2, alpha3beta2, alpha4beta4 and alpha3beta4), alpha-conotoxin MII (alpha3beta2) and alpha-conotoxin PnIA (alpha3beta2) reduced the nicotine effect. Nicotine- and epibatidine-induced currents were unaltered in beta2(-/-) mice, but in beta4(-/-) mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca(2+) -ATPase inhibitor) or the ryanodine receptor antagonists JTV-519 and dantrolene there was a reduction in the nicotine-effect, indicating involvement of Ca(2+) release from intracellular stores. Additionally, the PKA inhibitor H-89 and the TMEM16A (Ca(2+) -activated chloride channel) inhibitor T16Ainh-A01 significantly reduced the nicotine-effect. CONCLUSION AND IMPLICATIONS: alpha3beta4 nAChRs are responsible for the nicotine-induced current changes via Ca(2+) release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A. |
