@article {Roy2021.09.12.459939, author = {Ranjan K. Roy and Hildebrando Candido Ferreira-Neto and Robert B. Felder and Javier E. Stern}, title = {Angiotensin II Inhibits the A-type K+ Current of Hypothalamic Paraventricular Nucleus Neurons in Rats with Heart Failure: Role of MAPK-ERK1/2 Signaling}, elocation-id = {2021.09.12.459939}, year = {2021}, doi = {10.1101/2021.09.12.459939}, publisher = {Cold Spring Harbor Laboratory}, abstract = {ANGII-mediated sympathohumoral activation constitutes a key pathophysiological mechanism in heart failure (HF). While the hypothalamic paraventricular nucleus (PVN) is recognized as a major site mediating ANGII effects in HF, the precise mechanisms by which ANGII influences sympathohumoral outflow from the PVN remain unknown. ANGII activates the ubiquitous intracellular MAPK signaling cascades and recent studies revealed a key role for ERK1/2 MAPK signaling in ANGII-mediated sympathoexcitation in HF rats. Importantly, ERK1/2 was reported to inhibit the transient outward potassium current (IA) in hippocampal neurons. Given that IA is a critical determinant of the PVN neuronal excitability, and that downregulation of IA in the brain has been reported in cardiovascular disease states, including HF, we investigated here whether ANGII modulates IA in PVN neurons via the MAPK-ERK pathway, and, whether these effects are altered in HF rats. Patch-clamp recordings from identified magnocellular neurosecretory (MNNs) and presympathetic (PS) PVN neurons revealed that ANGII inhibited IA in both PVN neuronal types, both in sham and HF rats. Importantly, ANGII effects were blocked by inhibiting MAPK-ERK signaling as well as by inhibiting EGFR, a gateway to MAPK-ERK signaling. While no differences in basal IA magnitude were found between sham and HF rats under normal conditions, MAPK-ERK blockade resulted in significantly larger IA in both PVN neuronal types in HF rats. Taken together, our studies show that ANGII-induced ERK1/2 activity inhibits IA and increases the excitability of presympathetic and neuroendocrine PVN neurons, contributing to the neurohumoral overactivity than promotes progression of the HF syndrome.Competing Interest StatementDr. Robert Felder is party to a patent application for a novel microparticle drug preparation designed to counter central ERK1/2 activity and he is a consultant on an SBIR being submitted to pursue that idea}, URL = {https://www.biorxiv.org/content/early/2021/09/15/2021.09.12.459939}, eprint = {https://www.biorxiv.org/content/early/2021/09/15/2021.09.12.459939.full.pdf}, journal = {bioRxiv} }