The sympathetic drive emanating from the brain is increased in many pathophysiological conditions including hypertension and congestive heart failure. The paraventricular nucleus (PVN) of the hypothalamus is an important site for the control of sympathetic outflow through its projections to the sympathetically related sites in the brainstem and spinal cord. It has been shown that angiotensin II (Ang II) increases the excitability of PVN presympathetic neurons by attenuation of the synaptic GABA release. On the other hand, nitric oxide (NO) inhibits PVN presympathetic neurons through potentiation of the GABAergic input. However, the important signal transduction mechanisms responsible for the presynaptic actions of Ang II and NO remain poorly understood. In this proposal, PVN neurons that project to the rostral ventrolateral medulla and spinal intermediolateral cell column in rats will be used as a model system to test the following specific hypotheses: 1) Ang II reduces the GABAergic synaptic input to PVN presympathetic neurons through voltage-gated K+ channels activated by 12-lipoxygenase products and phospholipase A2 coupled to inhibitory G proteins; 2) Nitric oxide potentiates synaptic GABA release onto PVN presympathetic neurons through inhibition of voltage-gated K+ channels, due to activation of protein phosphatases by protein kinase G; and 3) Kv1/Kv4 subunits that form voltage-gated K+ channels are located on GABAergic presynaptic terminals in the PVN. These hypotheses will be tested using a combination of in vivo retrograde tracing, whole-cell patch-clamp recording in rat brain slices, and immunocytochemistry techniques. These studies will provide important new information about the fundamental cellular and signaling mechanisms for the opposing presynaptic actions of Ang II and NO in the central nervous system. This information also will be important for our understanding of the synaptic mechanisms responsible for central regulation of the sympathetic nervous system in physiological and pathophysiological states such as hypertension, myocardial infarction, and congestive heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL077400-01A1
Application #
6927567
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Velletri, Paul A
Project Start
2005-06-01
Project End
2006-03-31
Budget Start
2005-06-01
Budget End
2006-03-31
Support Year
1
Fiscal Year
2005
Total Cost
$350,223
Indirect Cost
Name
Pennsylvania State University
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Zhu, Yun; Chen, Shao-Rui; Pan, Hui-Lin (2016) Muscarinic receptor subtypes differentially control synaptic input and excitability of cerebellum-projecting medial vestibular nucleus neurons. J Neurochem 137:226-39
Zhou, Meng-Hua; Bavencoffe, Alexis; Pan, Hui-Lin (2015) Molecular Basis of Regulating High Voltage-Activated Calcium Channels by S-Nitrosylation. J Biol Chem 290:30616-23
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Li, De-Pei; Zhu, Li-Hong; Pachuau, Judith et al. (2014) mGluR5 Upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats. J Neurosci 34:4309-17
Ye, Zeng-You; Li, De-Pei; Pan, Hui-Lin (2013) Regulation of Hypothalamic Presympathetic Neurons and Sympathetic Outflow by Group II Metabotropic Glutamate Receptors in Spontaneously Hypertensive Rats. Hypertension 62:255-62
Ye, Zeng-You; Li, Li; Li, De-Pei et al. (2012) Casein kinase 2-mediated synaptic GluN2A up-regulation increases N-methyl-D-aspartate receptor activity and excitability of hypothalamic neurons in hypertension. J Biol Chem 287:17438-46
Li, De-Pei; Byan, Hee Sun; Pan, Hui-Lin (2012) Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension. J Neurosci 32:372-80

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