Cholinergic control of epidermal cohesion

Abstract

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.

Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction

“…Taken together, our data are in line with the hypothesis that direct inhibition of Dsg 3 transinteraction or activation of cellsignaling mechanisms may not be mutually exclusive but rather act in concert in pemphigus pathogenesis (42,43,49). Moreover, it is unlikely that direct inhibition of Dsg 3 transinteraction alone accounts for desmosomal splitting and acantholysis in PV.…”

Neuronal nicotinic alpha7 receptors modulate inflammatory cytokine production in the skin following ultraviolet radiation

“…Results are expressed as percent of a mouse housekeeping gene, GAPDH (TBP and β-actin have also been used with no difference in results, not shown). These results are in basic agreement with subunit expression in human epidermal and oral keratinocytes and human scalp tissue (Grando, 2006;Grando et al, 1995;Kurzen et al, 2007). We have also examined nAChR subunit expression in separated skin (epidermis separated from dermis using EDTA separation solutions (Sauder et al, 1982)) to determine if the dermis (composed of mostly fibroblasts and collagen) contributes to the nAChR subunit composition.…”

Desmosomes at a glance

“…Acute Ca 2+ depletion causes the engulfment of desmosomal plaques and associated IFs, whereas protein kinase inhibition prevents loss of adhesion and accompanying internalization (Garrod and Kimura, 2008). In addition, cholinergic receptors, receptor tyrosine kinases, proteolytic processing by ADAM (a disintegrin and metalloproteinase) sheddases and pathogenic pemphigus autoantibodies have all been implicated in junctional destabilization through their capacity to promote desmosomal cadherin internalization and/or to weaken interactions between desmosomal cadherins and IFs (Delva and Kowalczyk, 2009;Grando, 2006;Kottke et al, 2006;Muller et al, 2008;Waschke, 2008). Although PKC promotes desmosome assembly, its activity is attenuated during junctional maturation, leading to the formation of hyperadhesive Ca 2+ -independent desmosomes.…”