Figure 1.

Molecular mechanism of memantine action. (A) The memantine molecule acts as a blocker of the NMDAR ionic channel and it is able to regulate the synaptic dopamine concentration via the inhibition of the presynaptic dopamine transporter (DAT1) activity. Moreover, the blockade of the NMDAR function causes an upregulation of BDNF expression via the Erk, CamK, PI3K, and PLC signaling pathways. Memantine can inhibit inwardly rectifying potassium channels K_ir 6.1 and K_ir 6.2, and may also decrease voltage-gated calcium channels (VGCC)-dependent glutamate exocytosis. A synthesis of kynurenic acid is stimulated by memantine through the activation of protein kinase A (PKA). (B) Schematic NMDAR structure in the context of memantine action. Two receptor subunits (NR1 and NR2) are presented (transmembrane domains marked in blue and red, respectively) with their glycine and glutamate binding sites (ligand molecules included). Asparagine residues involved in channel blockade by Mg²⁺ and several inhibitors including memantine are shown. Based on Sing et al. (2018), modified. NMDAR—NMDA receptor; PKA—protein kinase A; PKC—protein kinase C; PLC—phospholipase C; Er—extracellular signal-regulated kinases; BDNF—brain derived neurotrophic factor; PI3K—phosphoinositide 3-kinase; CamK—calcium/calmodulin-dependent protein kinase. Up and down thick arrows indicate the direction of changes.