Angiotensin II (Ang II) plays a major role in the central nervous system in the regulation of memory, behavior, and learning. Centrally and peripherally, Ang II facilitates neurotransmission by enhancing norepinephrine (NE) release from catecholaminergic nerve terminals and prohibiting reuptake. Activation of Ang II type I (AT1) receptors in the hypothalamus and brainstem lead to physiological changes including increased drinking, increased baroreceptor function, and alterations in arterial pressure. Little information is available regarding the modulatory actions of Ang II on neuronal ionic currents which are the basis of neuronal action potentials. Knowledge of ionic current modulation by Ang II is therefore of great interest due to the fundamental importance of the frequency and firing patterns of action potentials to all physiological events mediated by a given neuron. Disruption of the intracellular signaling events responsible for the modulatory actions of Ang II would lead to alteration of neuronal activity. Due to its importance as an intracellular messenger and its role in neurotransmitter release, the specific aims set forth in this proposal focus on neuronal Ca2+ current and its modulation by Ang II through the AT1 receptor.
The aims are: 1) Biophysically and pharmacologically characterize the Ca2+ channels expressed in cultured neonatal rat hypothalamic neurons. 2) Determine which Ca2+ channel subtypes are modulated by Ang II. 3) Determine the intracellular pathways responsible for the Ang II modulation of Ca2+ current. 4) Compare and contrast the effects of Ca2+ channel blockers on Ang II and KC1-induced norepinephrine release. The results gathered from this study will help to elucidate the effects of Ang II on different neuronal Ca2+ channel subtypes and enhance our knowledge of the regulation of norepinephrine release in the brain and thus, the central control of arterial blood pressure.
