Dysregulation of brain
angiotensin II (AngII) signaling results in modulation of neuronal
ion channel activity, an increase in neuronal firing, enhanced sympathoexcitation, and subsequently elevated blood pressure. Studies over the past two decades have shown that these AngII responses are mediated, in part, by
reactive oxygen species (ROS). However, the redox-sensitive target(s) that are directly acted upon by these ROS to execute the AngII pathophysiological responses in neurons remain unclear.
Calcium/calmodulin-dependent protein kinase II (
CaMKII) is an AngII-activated intra-neuronal signaling
protein, which has been suggested to be redox sensitive as overexpressing the
antioxidant enzyme superoxide dismutase attenuates AngII-induced activation of
CaMKII. Herein, we hypothesized that the neuronal
isoform of
CaMKII,
CaMKII-alpha (CaMKIIα), is a redox-sensitive target of AngII, and that mutation of potentially redox-sensitive
amino acids in CaMKIIα influences AngII-mediated intra-neuronal signaling and
hypertension. Adenoviral vectors expressing wild-type mouse CaMKIIα (Ad.wtCaMKIIα) or mutant CaMKIIα (Ad.mutCaMKIIα) with C280A and M281V mutations were generated to overexpress either CaMKIIα
isoform in mouse catecholaminergic cultured neurons (CATH.a) or in the brain subfornical organ (SFO) of hypertensive mice. Overexpressing wtCaMKIIα exacerbated AngII pathophysiological responses as observed by a potentiation of AngII-induced inhibition of voltage-gated K+ current, enhanced in vivo pressor response following intracerebroventricular injection of AngII, and sensitization to chronic peripheral infusion of AngII resulting in a more rapid increase in blood pressure. In contrast, expressing the mutant CaMKIIα in CATH.a neurons or the SFO failed to intensify these AngII responses. Taken together, these data identify neuronal CaMKIIα as a redox-sensitive signaling
protein that contributes to AngII-induced neuronal activation and
hypertension.