406 Modulation of calcium channel activity in Darier’s disease keratinocytes improves disease phenotypes

Darier’s disease (DD) is an autosomal dominant skin disorder characterized by acantholysis and dyskeratosis associated with mutations in ATP2A2 encoding for the sarco/endoplasmic reticulum Ca2+-ATPase pump type 2 (SERCA2), resulting patients being functionally haploinsufficient SERCA2. DD keratinocytes displayed a 1.5-fold increase Ca2+ levels above that observed control keratinocytes. This imbalance negatively influenced localization of protein constituents cell-cell adhesive junction, desmosome, decreased desmosome function loss epidermal integrity. Toward resolving imbalance, controls were treated pharmacological SERCA2 activator, CDN1163. CDN1163 treatment cells increased border components plakophilin 3 desmoplakin 2-fold DMSO treatment, restoring formation to level Desmosome uniformity along cell borders was enhanced 2.5-fold Correspondingly, strength restored, evaluated measurement monolayer integrity upon challenge mechanical stress. As second approach, we utilized compound dantrolene sodium, administered clinically as muscle relaxant spasticity CNS disorders such multiple sclerosis, cerebral palsy stroke. Dantrolene acts dampen activity Ryanodine receptors, SR/ER pumps responsible regulating release from ER stores. resulted at restoration These results highlight potential drugs designed balance epidermis promising avenues therapeutic intervention reduce severity.