NMDA-type glutamate receptor is associated with cutaneous barrier homeostasis

Glutamate receptors play an important role in the excitatory synaptic action of the central nervous system. In this study, effects of glutamate receptor agonists and antagonists on skin barrier homeostasis were studied using hairless mouse. Topical application of L-glutamic acid, L-aspartic acid (non-specific glutamate receptor agonists) and N-methyl-D-aspartate (NMDA, NMDA type receptor agonist) delayed the barrier recovery rate after barrier disruption with tape stripping. On the other hand, topical application of D-glutamic acid (non-specific antagonist of glutamate receptor), MK 801 and D-AP5, (NMDA-type receptor antagonists) accelerated the barrier repair. The non-NMDA type receptor agonist, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), did not affect the barrier recovery. Topical application of MK-801 also promoted the healing of epidermal hyperplasia induced by acetone treatment under low environmental humidity. Immediately after barrier disruption on skin organ culture, secretion of glutamic acid from skin was significantly increased. Immunohistochemistry, reverse transcription polymearse chain reaction (RT-PCR) and in situ hybridization showed an expression of NMDA-type receptor-like protein on hairless mouse epidermis. NMDA increased intercellular calcium in cultured human keratinocytes and the increase was blocked by MK 801. These results suggest that glutamate plays an important role as a signal of cutaneous barrier homeostasis and epidermal hyperplasia induced by barrier disruption.