Functional NMDA receptors with atypical properties are expressed in podocytes.

N-methyl-D-aspartate (NMDA) receptors are essential for normal nervous system function, but their excessive activation can lead to neuronal degeneration. NMDA receptors are also expressed in peripheral tissues, where their properties and significance are not well understood. Here we show that functional NMDA receptors are expressed in podocytes, polarized cells that form an essential component of the glomerular filtration apparatus. Application of NMDA to podocyte cell lines or primary cultures of mouse podocytes evoked macroscopic currents mediated by cation channels, with significant permeability to Ca²(+). Podocyte NMDA receptors do not desensitize with prolonged exposure to NMDA. They are blocked by supraphysiological concentrations of external or internal Mg²(+) and, also, by the prototype antagonists MK-801 and D-2-aminophosphonovaleric acid. NMDA responses in podocytes were strongly potentiated by D-serine, but not by glycine, even at high concentrations. D-Aspartate and L-homocysteate are effective agonists of podocyte NMDA receptors. Surprisingly, L-glutamate and L-aspartate did not evoke robust ionic currents in podocytes, regardless of the concentration or membrane potential at which these amino acids were tested. NMDA application for 2 h caused activation of secondary signals through Erk and Akt pathways and, at higher concentrations, caused activation of RhoA. Exposure to NMDA for 6 h did not cause loss of cultured podocytes but did lead to a reduction in nephrin expression. NMDA receptors that respond to circulating ligands may play a role in regulation of glomerular function or dysfunction, but they are unlikely to be components of a local glutamate signaling system in glomeruli.