Dopamine D2-like receptor agonists accelerate barrier repair and inhibit the epidermal hyperplasia induced by barrier disruption

Two families of G protein-coupled receptors of the neurotransmitter dopamine, i.e., dopamine 1-like family (D1-like receptor) and dopamine 2-like family (D2-like receptor), show dopaminergic activity in nerve cells. The D2-like receptor family, composed of D2, D3, and D4 receptors, downregulates the intracellular cAMP signaling pathway, and dopamine receptor agonists reduce the cAMP level in neurons. We previously demonstrated that the cAMP level in epidermal keratinocytes is related to epidermal barrier homeostasis. Since keratinocytes are known to carry various neurotransmitter receptors, we hypothesized that D2-like receptors on keratinocytes might be related to skin barrier homeostasis. In this study, we examined the effect of topical application of receptor agonists and antagonists on skin barrier recovery after barrier disruption. Application of D2-like receptor agonists accelerated barrier recovery, whereas D2-like receptor antagonists delayed it. D2-like receptor agonists also reduced the epidermal hyperplasia induced by barrier disruption under low environmental humidity. Immunohistochemical study and RT-PCR analysis revealed the expression of the D2 receptor in the basal epidermis and the D4 receptor in the uppermost layer of the epidermis. These results suggest that dopaminergic receptors are involved in epidermal barrier homeostasis.