β-Adrenergic Receptor Trafficking, Degradation, and Cell Surface Expression Are Altered in Dermal Fibroblasts from Hypertrophic Scars

Burn trauma elevates catecholamines for up to 2 years and causes hypertrophic scarring. Propranolol, a nonspecific beta 1-, beta 2-adrenergic receptor (AR) inverse agonist, counters the hypermetabolic response to elevated catecholamines and may decrease hypertrophic scarring by an unknown mechanism. We investigated the effect of burn injury on beta 1-, beta 2-, and beta 3-AR expression, trafficking, and degradation in human dermal fibroblasts from hypertrophic scar [HSF], non-scar fibroblasts, and normal fibroblasts. We also investigated the modulation of these events by propranolol. Catecholamine-stimulated cAMP production was lower in HSFs and non-scar fibroblasts than in normal fibroblasts. beta 1- and beta 2-AR cell surface expression was lowest in HSFs, but propranolol increased cell surface expression of these receptors. Basal beta 2-AR ubiquitination was higher in HSFs than non-scar or normal fibroblasts, suggesting accelerated receptor degradation. beta-AR degradation was mainly driven by lysosomal-specific polyubiquitination at Lys-63 in normal fibroblasts and HSFs, which was abrogated by propranolol. Propranolol also targeted beta-AR to the proteasome in HSFs. Confocal imaging showed a lack of beta 2-AR-GFP trafficking to lysosomal compartments in catecholamine-stimulated HSFs. These data suggest that burn trauma alters the expression, trafficking, and degradation of beta-ARs in dermal fibroblasts, which may then affect fibroblast responses to propranolol.