Contribution of α7 nicotinic receptor to airway epithelium dysfunction under nicotine exposure

Abstract

Loss or dysfunction of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) leads to impairment of airway mucus transport and to chronic lung diseases resulting in progressive respiratory failure. Nicotinic acetylcholine receptors (nAChRs) bind nicotine and nicotine-derived nitrosamines and thus mediate many of the tobacco-related deleterious effects in the lung. Here we identify α7 nAChR as a key regulator of CFTR in the airways. The airway epithelium in α7 knockout mice is characterized by a higher transepithelial potential difference, an increase of amiloride-sensitive apical Na + absorption, a defective cAMP-dependent Cl − conductance, higher concentrations of Na + , Cl − , K + , and Ca 2+ in secretions, and a decreased mucus transport, all relevant to a deficient CFTR activity. Moreover, prolonged nicotine exposure mimics the absence of α7 nAChR in mice or its inactivation in vitro in human airway epithelial cell cultures. The functional coupling of α7 nAChR to CFTR occurs through Ca 2+ entry and activation of adenylyl cyclases, protein kinase A, and PKC. α7 nAChR, CFTR, and adenylyl cyclase-1 are physically and functionally associated in a macromolecular complex within lipid rafts at the apical membrane of surface and glandular airway epithelium. This study establishes the potential role of α7 nAChR in the regulation of CFTR function and in the pathogenesis of smoking-related chronic lung diseases.chloride efflux | ciliated cell | mouse | mucociliary clearance | submucosal gland

Association of Gallbladder Mucocele Histologic Diagnosis with Selected Drug Use in Dogs: A Matched Case‐Control Study

“…Moreover, a number of nonneuronal cells, including T cells, macrophages, and airway epithelial cells, express nAChRs and may synthesize acetylcholine 27. Although not yet examined for gallbladder epithelium, in the airway nAChRs are expressed by epithelial cells28, 29 and nicotine has been demonstrated to decrease mucus transport,30 increase mucin expression and mucus secretion,31, 32 alter mucus hydration, and increase the viscosity of mucus 33. Nicotine also has been described to cause relaxation of guinea pig gallbladder by a mechanism independent of nAChRs 34.…”

The orphan pentameric ligand-gated ion channelpHCl-2is gated by pH and regulates fluid secretion inDrosophilaMalpighian tubules

“…While such non-neuronal roles of the GABA and glycine receptors are poorly understood, the α7 nicotinic acetylcholine receptor (nAChR) is expressed in macrophages where it regulates tumour necrosis factor-α in response to acetylcholine released from spleen lymphocytes (Rosas-Ballina et al, 2011). nAChR function has also been reported in bronchial epithelia, where nAChRs expressed on the apical membrane (Maus et al, 1998) respond to non-neuronal autocrine/paracrine ACh release to regulate chloride permeability through the cystic fibrosis transmembrane conductance regulator (CFTR) channel (Maouche et al, 2013). Nonneural roles for nAChRs have also been identified in vascular endothelia (reviewed in Egleton et al, 2009), in urothelia (Zarghooni et al, 2007) and in keratinocytes (Grando et al, 1995).…”

Presynaptic α7 Nicotinic Acetylcholine Receptors Enhance Hippocampal Mossy Fiber Glutamatergic Transmission via PKA Activation

“…Moreover, inhibition of PKA activity blocked the nAChR-mediated effect on synaptic plasticity in the hippocampus (Welsby et al, 2009). Recently, the ␣7 nAChR and adenylyl cyclase 1 (AC1) were shown to be associated physically and functionally in epithelium (Maouche et al, 2013). Stimulated by both calcium and calmodulin, AC1 is a suitable candidate to couple the ␣7 nAChR to PKA.…”