Basic and Clinical Aspects of Non-neuronal Acetylcholine: Biological and Clinical Significance of Non-canonical Ligands of Epithelial Nicotinic Acetylcholine Receptors

Abstract

Abstract. Mucocutaneous keratinocytes and bronchial epithelial cells express nicotinic acetylcholine receptors (nAChRs). Emerging evidence indicates that nAChRs can be stimulated also by the tobacco-derived nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) that can induce tumors in laboratory animals. Nitrosamines may disturb the delicate balance between cell proliferation, growth arrest, and apoptosis. A novel paradigm of cell regulation via nAChR has been discovered in studies of SLURP (secreted mammalian Ly-6/ urokinase plasminogen activator receptor-related protein)-1 and -2. Experimental results suggest that SLURP-1 and -2 regulate keratinocyte proliferation, apoptosis, and differentiation. Most importantly, SLURPs and professional nicotinic antagonists can abolish, in part, the abilities of NNK and NNN to cause tumorigenic transformation of immortalized keratinocytes. Learning the pharmacology of the nitrosamine vs. SLURP action on epithelial cells may help develop an effective anti-cancer treatment and prevention programs wherein hazardous effects of tobacco products are anticipated, or even abolished, by a pharmacologic ligand of the specific nicotinic receptor acting as an antidote.

Structural and functional diversity of native brain neuronal nicotinic receptors

“…The subunits have been cloned from neuron-like cells or cDNA libraries obtained from vertebrate brain, but it has recently been shown that some of them are expressed by non-neuronal cell types throughout the body and have various functions. However, the nAChRs expressed in non-neuronal tissues are beyond the scope of this review and interested readers are referred elsewhere [17][18][19][20][21].…”

Crooked, Coiled and Crimpled are three Ly6-like proteins required for proper localization of septate junction components

“…Reflecting their differential expression, Ly6 proteins are used in diverse biological processes. Apart from acting as GPI-linked cell accessory proteins of the immune system, vertebrate Ly6 proteins function in the modulation of nicotinic acetylcholine receptors (Choo et al, 2008;Darvas et al, 2009;Grando, 2008;Levitin et al, 2008;Liu et al, 2009), remodelling of the extracellular matrix during skeletal muscle regeneration (Kafadar et al, 2009), self-renewal of erythroid progenitors (Bresson-Mazet et al, 2008), and lipolytic processing of triglyceride-rich lipoproteins by binding lipoprotein lipase (Beigneux et al, 2009). The presence of a GPI-anchor in Ly6 molecules, a lipid anchor that tethers the proteins on the outer leaflet of the membrane, also suggests that Ly6 proteins can aggregate in lipid rafts to alter the activity of associated proteins (Bamezai, 2004;Halova et al, 2002).…”

Basic and Clinical Aspects of Non-neuronal Acetylcholine: Overview of Non-neuronal Cholinergic Systems and Their Biological Significance

“…In addition, the biological and clinical significance of epithelial nAChRs is discussed later in this issue (21). ACh synthesis in keratinocytes is catalyzed by ChAT, while its degradation is catalyzed by AChE (20,22,23).…”