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α2δ‐1 Is Essential for Angiotensin II‐Induced Sympathoexcitation and NMDA Receptor Hyperactivity in the Hypothalamus
Author(s) -
Ma Huijie,
Chen ShaoRui,
Chen Hong,
Zhou JingJing,
Li DePei,
Pan HuiLin
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.732.4
Subject(s) - nmda receptor , medicine , endocrinology , hypothalamus , excitatory postsynaptic potential , postsynaptic potential , glutamate receptor , chemistry , neuroscience , receptor , biology
Both the sympathetic nervous system and renin‐angiotensin system are critically involved in hypertension development. Although angiotensin II (Ang II) stimulates presympathetic neurons in the hypothalamic paraventricular nucleus (PVN) to increase sympathetic vasomotor tone, the molecular mechanism responsible for this action remains unclear. The glutamate N ‐methyl‐ D‐ aspartate receptor (NMDAR) in the PVN controls sympathetic outflow in hypertension. In this study, we determined how Ang II affects synaptic NMDARs in spinally projecting PVN neurons. Coimmunoprecipitation assays showed that α2δ‐1, commonly known as a voltage‐gated calcium channel subunit, interacted with the NMDAR in the hypothalamus of rats and humans. Ang II increased the synaptic expression level of α2δ‐1–NMDAR complexes. Also, Ang II increased pre‐ and postsynaptic NMDAR activity via AT1 receptors, and such effects were abolished either by treatment with pregabalin, an inhibitory α2δ‐1 ligand, or by interrupting the α2δ‐1–NMDAR interaction with α2δ‐1Tat peptide. In α2δ‐1 knockout mice, Ang II failed to affect the pre‐ and postsynaptic NMDAR activity of PVN neurons. In addition, the α2δ‐1Tat peptide blocked the sympathoexcitatory response to the microinjection of Ang II into the PVN. Our findings indicate that by promoting the synaptic trafficking of α2δ‐1–bound NMDARs, Ang II augments sympathetic vasomotor tone and excitatory glutamatergic input to PVN presympathetic neurons. Support or Funding Information This work was supported by the National Institutes of Health (Grant R01 HL131161) and the N.G. and Helen T. Hawkins Endowment (to H.‐L.P.). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .