Angiotensin II Decreases Neuronal Delayed Rectifier Potassium Current: Role of Calcium/Calmodulin-Dependent Protein Kinase II

Department of Physiology, College of Medicine, and University of Florida Brain Institute, University of Florida, Gainesville, Florida 32610 Zhu, Mingyan, Craig H. Gelband, Philip Posner, and Colin Sumners. Angiotensin II Decreases Neuronal Delayed Rectifier Potassium Current: Role of Calcium/Calmodulin-Dependent Protein Kinase II. J. Neurophysiol. 82: 1560-1568, 1999. 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 Ang II type 1 (AT 1 ) receptors and involve modulation of membrane ionic currents and neuronal activity. In previous studies we utilized neurons cultured 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, and that this effect is partially due to activation of protein kinase C (PKC), specifically PKC . However, the data also indicated that another Ca 2+ -dependent mechanism was also involved in addition to PKC. Because Ca 2+ /calmodulin-dependent protein kinase II (CaM KII) is a known modulator of K + currents in neurons, we investigated the role of this enzyme in the AT 1 receptor-mediated reduction of neuronal Kv current by Ang II. The reduction of neuronal Kv current by Ang II was attenuated by selective inhibition of either calmodulin or CaM KII and was mimicked by intracellular application of activated (autothiophosphorylated) CaM KII . Concurrent inhibition of CaM KII and PKC completely abolished the reduction of neuronal Kv by Ang II. Consistent with these findings is the demonstration that Ang II increases CaM KII activity in neuronal cultures, as evidenced by increased levels of autophosphorylated CaM KII subunit. Last, single-cell reverse transcriptase (RT)-PCR analysis revealed the presence of AT 1 receptor-, CaM KII -, and PKC subunit mRNAs in neurons that responded to Ang II with a decrease in Kv current. The present data indicate that the AT 1 receptor-mediated reduction of neuronal Kv current by Ang II involves a Ca 2+ /calmodulin/CaM KII pathway, in addition to the previously documented involvement of PKC.