My. Zhu et al., Angiotensin II decreases neuronal delayed rectifier potassium current: Role of calcium/calmodulin-dependent protein kinase II, J NEUROPHYS, 82(3), 1999, pp. 1560-1568
Angiotensin II(Ang II) acts at specific receptors located on neurons in the
hypothalamus and brain stem to elicit alterations in blood pressure, fluid
intake, and hormone secretion. These actions of Ang II. are mediated via A
ng II type 1 (AT(1)) receptors and involve modulation of membrane ionic cur
rents and neuronal activity. In previous studies we utilized neurons cultur
ed from the hypothalamus and brain stem of newborn rats to investigate the
AT(1) receptor-mediated effects of Ang II on neuronal K+ currents. Our data
indicate that Ang II decreases neuronal delayed rectifier (Kv) current, an
d that this effect is partially due to activation of protein kinase C (PKC)
,specifically PKC alpha. However, the data also indicated that another Ca2-dependent mechanism was also involved in addition to PKC. Because Ca2+/cal
modulin-dependent protein kinase II (CaM KII) is a known modulator of K+ cu
rrents in neurons, we investigated the role of this enzyme in the AT(1) rec
eptor-mediated reduction of neuronal Ky current by Ang II. The reduction of
neuronal Ky current by Ang II was attenuated by selective inhibition of ei
ther calmodulin or CaM KII and was mimicked by intracellular application of
activated (autothiophosphorylated) CaM KII alpha. Concurrent inhibition of
CaM KII and PKC completely abolished the reduction of neuronal Ky by Ang I
I. Consistent with these findings is the demonstration that Ang II increase
s CaM KII activity in neuronal cultures, as evidenced by increased levels o
f autophosphorylated CaM KII alpha subunit. Last, single-cell reverse trans
criptase (RT)-PCR analysis revealed the presence of AT(1) receptor-, CaM KI
I alpha-, and PKC alpha subunit mRNAs in neurons that responded to Ang II w
ith a decrease in Ky current. The present data indicate that the AT(1) rece
ptor-mediated reduction of neuronal Ky current by Ang II involves a Ca2+/ca
lmodulin/CaM KII pathway, in addition to the previously documented involvem
ent of PKC.