α2δ‐1 couples to NMDA receptors in the hypothalamus to sustain sympathetic vasomotor activity in hypertension

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.

Endogenous AT1 receptor–protein kinase C activity in the hypothalamus augments glutamatergic input and sympathetic outflow in hypertension

“…; Ma et al . ). We thus investigated whether the endogenous AT1 receptor and PKC activity play a role in the increased postsynaptic NMDAR activity of spinally projecting PVN neurons in SHRs.…”

“…; Ma et al . , b ). Exogenous AngII application stimulates presynaptic NMDARs via AT1 receptors in the PVN (Ma et al .…”

“…; Ma et al . ). Since the protein binding complexes are strengthened by increased protein phosphorylation through changes in their physicochemical properties, stability and dynamics (Nishi et al .…”

“…Additionally, synaptic NMDAR hyperactivity in the PVN is due to the increased α2δ‐1–NMDAR coupling in SHRs (Ma et al . , b ), and targeting α2δ‐1‐bound NMDARs with a specific peptide in the PVN or with systemic gabapentin administration reduces ABP in SHRs (Behuliak et al . ; Ma et al .…”

“…; Ma et al . ). The RVLM tissues were bilaterally punched out in accordance with the stereotactic coordinates: 12.5–13.0 mm caudal to the bregma, 1.9–2.0 mm lateral to the midline and 7.5–8.0 mm ventral to the dura.…”