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α2δ-1 couples to NMDA receptors in the hypothalamus to sustain sympathetic vasomotor activity in hypertension.
- Source :
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The Journal of physiology [J Physiol] 2018 Sep; Vol. 596 (17), pp. 4269-4283. Date of Electronic Publication: 2018 Jul 30. - Publication Year :
- 2018
-
Abstract
- Key Points: α2δ-1 is upregulated, promoting the interaction with NMDA receptors (NMDARs), in the hypothalamus in a rat model of hypertension. The prevalence of α2δ-1-bound NMDARs at synaptic sites in the hypothalamus is increased in hypertensive animals. α2δ-1 is essential for the increased presynaptic and postsynaptic NMDAR activity of hypothalamic neurons in hypertension. α2δ-1-bound NMDARs in the hypothalamus are critically involved in augmented sympathetic outflow in hypertensive animals.<br />Abstract: Increased glutamate NMDA receptor (NMDAR) activity in the paraventricular nucleus (PVN) of the hypothalamus leads to augmented sympathetic outflow in hypertension. However, the molecular mechanisms underlying this effect remain unclear. α2δ-1, previously considered to be a voltage-activated calcium channel subunit, is a newly discovered powerful regulator of NMDARs. In the present study, we determined the role of α2δ-1 in regulating synaptic NMDAR activity of rostral ventrolateral medulla (RVLM)-projecting PVN neurons in spontaneously hypertensive rats (SHRs). We show that the protein levels of α2δ-1 and NMDARs in synaptosomes and the α2δ-1-NMDAR complexes in the hypothalamus were substantially higher in SHRs than in normotensive control rats. The basal amplitude of evoked NMDAR currents and NMDAR-mediated synaptic glutamate release in RVLM-projecting PVN neurons were significantly increased in SHRs. Strikingly, inhibiting α2δ-1 activity with gabapentin or disrupting the α2δ-1-NMDAR association with an α2δ-1 C-terminus peptide completely normalized the amplitude of evoked NMDAR currents and NMDAR-mediated synaptic glutamate release in RVLM-projecting PVN neurons in SHRs. In addition, microinjection of the α2δ-1 C-terminus peptide into the PVN substantially reduced arterial blood pressure and renal sympathetic nerve discharges in SHRs. Our findings indicate that α2δ-1-bound NMDARs in the PVN are required for the potentiated presynaptic and postsynaptic NMDAR activity of PVN presympathetic neurons and for the elevated sympathetic outflow in hypertension. α2δ-1-bound NMDARs may be an opportune target for treating neurogenic hypertension.<br /> (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)
- Subjects :
- Animals
Glutamic Acid metabolism
Male
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Calcium Channels, L-Type metabolism
Excitatory Postsynaptic Potentials
Hypertension physiopathology
Hypothalamus physiopathology
Paraventricular Hypothalamic Nucleus physiopathology
Receptors, N-Methyl-D-Aspartate metabolism
Sympathetic Nervous System physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1469-7793
- Volume :
- 596
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- The Journal of physiology
- Publication Type :
- Academic Journal
- Accession number :
- 29971791
- Full Text :
- https://doi.org/10.1113/JP276394