(TKP2021-EGA-23) Támogató: Innovációs és Technológiai Minisztérium
(TKP2021-EGA-25)
Szakterületek:
Gyógyszerészet, farmakogenomika, gyógyszerkutatás és tervezés, gyógyszeres kezelés
Background: N-methyl-D-aspartate type glutamate receptors (NMDARs) are fundamental
to neuronal physiology and pathophysiology. The prefrontal cortex (PFC), a key region
for cognitive function, is heavily implicated in neuropsychiatric disorders, positioning
the modulation of its glutamatergic neurotransmission as a promising therapeutic target.
Our recently published findings indicate that AT1 receptor activation enhances NMDAR
activity in layer V pyramidal neurons of the rat PFC. At the same time, it suggests
that alternative angiotensin pathways, presumably involving AT4 receptors (AT4Rs),
might exert inhibitory effects. Angiotensin IV (Ang IV) and its analogs have demonstrated
cognitive benefits in animal models of learning and memory deficits. Methods: Immunohistochemistry
and whole-cell patch-clamp techniques were used to map the cell-type-specific localization
of AT4R, identical to insulin-regulated aminopeptidase (IRAP), and to investigate
the modulatory effects of Ang IV on NMDAR function in layer V pyramidal cells of the
rat PFC. Results: AT4R/IRAP expression was detected in pyramidal cells and GABAergic
interneurons, but not in microglia or astrocytes, in layer V of the PFC in 9–12-day-old
and 6-month-old rats. NMDA (30 μM) induced stable inward cation currents, significantly
inhibited by Ang IV (1 nM–1 µM) in a subset of pyramidal neurons. This inhibition
was reproduced by the IRAP inhibitor LVVYP-H7 (10–100 nM). Synaptic isolation of pyramidal
neurons did not affect the Ang IV-mediated inhibition of NMDA currents. Conclusions:
Ang IV/IRAP-mediated inhibition of NMDA currents in layer V pyramidal neurons of the
PFC may represent a way of regulating cognitive functions and thus a potential pharmacological
target for cognitive impairments and related neuropsychiatric disorders.
