AT4 receptor activation increases intracellular calcium influx and induces a non-N-methyl-D-aspartate dependent form of long-term potentiation

The angiotensin 4 receptor (AT(4)) 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. Our laboratory previously demonstrated that application of the AT(4) agonist, Norleucine(1)-angiotensin IV, enhanced baseline synaptic transmission and long-term potentiation, whereas perfusion with the AT(4) antagonist, Norleucine(1)-Leu(3-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 Norleucine(1)-angiotensin IV-induced increase in hippocampal long-term potentiation. Hippocampal slices perfused with Norleucinel-angiotensin IV for 20 min revealed a notable increase in baseline responses in a nonreversible manner and were blocked by the alpha-amino-3-hydroxy5-methyl-4-isoxazole propionate receptor antagonist, 6-cyano7-nitroquinoxaline-2,3-dione disodium salt. Infusions of Norleucine(1)-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 Norleucine(1)-angiotensin IV in the presence of the N-methyl-D-asparate antagonist, D,L-2-amino5-phosphonovaleric acid. Blockade of select voltage dependent calcium channels significantly reduced Norleucine(1)-angiotensin IV-induced increase in baseline responses and subsequent long-term potentiation suggesting that AT(4) 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 Nle(1)-angiotensin IV to cultured rat hippocampal neurons resulted in increased intracellular calcium derived exclusively from extracellular sources. Consistent with these observations Nle(1)-angiotensin IV was capable of augmenting the uptake of 45 Ca2+ into rat hippocampal slices. Taken together, these data indicate that increased calcium influx through postsynaptic calcium channels contribute to Norleucine(1)-angiotensin IV-induced enhancement of long-term potentiation. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.