The angiotensin 4 receptor (AT4) subtype is heavily distributed in the dentate gyrus and CA1-CA3 subfields of the hippocampus. Neuronal pathways connecting these subfields are believed to be activated during learning and memory processing. ur laboratory previously demonstrated that application of the AT4 agonist, Norleucine1-angiotensin IV, enhanced baseline synaptic transmission and long-term potentiation, whereas perfusion with the AT4 antagonist, Norleucine1-Leu3-psi(CH2-NH2)3-4-angiotensin IV disrupted long-term potentiation stabilization in area CA1. The objective of the present study was to identify the mechanism(s) responsible for Norleucine1-angiotensin IV-induced increase in hippocampal long-term potentiation. Hippocampal slices perfused with Norleucine1-angiotensin IV for 20 min revealed a notable increase in baseline responses in a non-reversible manner and were blocked by the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt. Infusions of Norleucine1-angiotensin IV prior to, but not after theta burst stimulation, significantly enhanced long-term potentiation compared with control slices. Further, N-methyl-D-aspartate receptor-independent long-term potentiation could be induced by tetanization during the perfusion of Norleucine1-angiotensin IV in the presence of the N-methyl-D-aspartate antagonist, D,L-2-amino-5-phosphonovaleric acid. Blockade of select voltage dependent calcium channels significantly reduced Norleucine1-angiotensin IV-induced increase in baseline responses and subsequent long-term potentiation suggesting that AT4 receptor activation increases intracellular calcium levels via altering voltage dependent calcium channels and triggers an N-methyl-D-aspartate-independent form of long-term potentiation. In support of this notion the application of Nle1-angiotensin IV to cultured rat hippocampal neurons resulted in increased intracellular calcium derived exclusively from extracellular sources. Consistent with these observations Nle1-angiotensin IV was capable of augmenting the uptake of 45Ca2+ into rat hippocampal slices. Taken together, these data indicate that increased calcium influx through postsynaptic calcium channels contribute to Norleucine1-angiotensin IV-induced enhancement of long-term potentiation.