Schwann cells of the peripheral nervous system are distinguished by morphological and functional criteria in myelinating and non-myelinating subtypes. We and others have previously reported that Schwann cells in isolated peripheral human and rat nerve respond to extracellular application of ATP with a rise in the intracellular free calcium concentration [Ca2+]i. In the present study, the receptors mediating these Ca2+ transients have been investigated in myelinating and non-myelinating Schwann cells of intact fascicles of isolated human sural nerves, rat ventral roots, and rat vagus nerves. Microfluorometry and confocal laser scanning was used on preparations stained with the Ca2+-sensitive dyes Calcium Green-1 and Fura Red. In myelinating Schwann cells of human and rat nerves, the ATP-induced rise of [Ca2+]i resulted from the activation of a P2Y2 purinoceptor subtype (rank order of potency: UTP > or = ATP >> 2-MeSATP = ADP). In contrast, in non-myelinating Schwann cells, Ca2+ transients were produced by activation of a P2Y1 purinoceptor subtype (rank order of potency: 2-MeSATP > ATP > ADP >> UTP). The P1 agonist adenosine and alpha,alpha-meATP did not evoke Ca2+ signals. Ca2+ transients in both types of Schwann cells were found to be due to Ca2+ release from cyclopiazonic acid-sensitive intracellular stores. However, inhibition by suramin was only found in non-myelinating Schwann cells. These findings indicate that mammalian Schwann cells express phenotype-specific P2Y receptor subtypes.