Extracellular ATP via the activation of purinergic P2 receptors has an emerging role in cutaneous biology; however, the distribution of these receptors in mouse skin is poorly defined. This study investigated whether murine epidermal cell subpopulations express functional purinergic P2X(7) receptors. P2X(7) expression was examined by immunoblotting and immunofluorescence staining of epidermal cells from C57Bl/6 mice. P2X(7) function was evaluated by nucleotide-induced ethidium+ uptake measurements in epidermal cells from C57Bl/6 mice, and from P2X(7) deficient mice and wild-type littermate controls. P2X(7) was detected in whole epidermal cell preparations, and specifically on Langerhans cells (LCs) and keratinocytes (KCs). ATP induced ethidium+ uptake into LCs and KCs, with EC50 values of 503 and 482 mu m, respectively. BzATP, and to a lesser extent ATP gamma S and ADP, also induced ethidium+ uptake; while UTP, alpha beta-meth-ATP and NAD were ineffective. ATP-induced ethidium+ uptake was impaired by Na+ and Mg2+, and the P2X(7) antagonist, A-438079 and was absent in LCs and KCs from P2X(7) deficient mice. These results demonstrate that murine LCs and KCs express functional P2X(7), and support a role for this receptor in cutaneous biology.