Cholinergic control of epidermal cohesion

The non-neuronal cholinergic system of human epidermis includes the keratinocyte (KC) acetylcholine (ACh) axis composed of the enzymes mediating ACh synthesis and degradation, and two classes of ACh receptors, the nicotinic and muscarinic ACh receptors, mediating biological effects of the cutaneous cytotransmitter ACh. Regulation of KC cell-cell and cell-matrix adhesion is one of the important biological functions of cutaneous ACh. The downstream targets of ACh effects mediated by distinct ACh receptor subtypes include both the intercellular adhesion molecules, such as classical and desmosomal cadherins, and integrins mediating KC adhesion to a substrate. The signaling pathways include activation or inhibition of kinase cascades resulting in either up- or down-regulation of the expression of cell adhesion molecules or changes in their phosphorylation status, or both. The components of the KC ACh axis are involved in cutaneous blistering in patients with autoimmune pemphigus, junctional and dystrophic forms of epidermolysis bullosa, thermal burns, and mustard-induced vesication. Recent progress with the development of antiacantholytic therapies of patients with pemphigus using cholinomimetics indicates that cholinergic drugs may be a promising approach for other cutaneous blistering disorders.