LAUSR

Glutamate AMPA receptors (AMPARs) lacking GluA2 subunit are calcium permeable (CP‐AMPARs), which are increased in the hypothalamic paraventricular nucleus (PVN) and maintain sympathetic outflow in hypertension. Here, we determined the role of α2δ‐1, an NMDA receptor–interacting protein, in regulating synaptic CP‐AMPARs in the hypothalamus in spontaneously hypertensive rats (SHR). Co‐immunoprecipitation showed that levels of GluA1/GluA2, but not GluA2/GluA3, protein complexes in hypothalamic synaptosomes were reduced in SHR compared with Wistar–Kyoto rats (WKY). The level of GluA1/GluA2 heteromers in endoplasmic reticulum‐enriched fractions of the hypothalamus was significantly lower in SHR than in WKY, which was restored by inhibiting α2δ‐1 with gabapentin. Gabapentin also switched AMPAR‐mediated excitatory postsynaptic currents (AMPAR‐EPSCs) from inward rectifying to linear and attenuated the inhibitory effect of IEM‐1460, a selective CP‐AMPAR blocker, on AMPAR‐EPSCs in spinally projecting PVN neurons in SHR. Furthermore, co‐immunoprecipitation revealed that α2δ‐1 directly interacted with GluA1 and GluA2 in the hypothalamus of rats and humans. Levels of α2δ‐1/GluA1 and α2δ‐1/GluA2 protein complexes in the hypothalamus were significantly greater in SHR than in WKY. Disrupting the α2δ‐1–AMPAR interaction with an α2δ‐1 C terminus peptide normalized GluA1/GluA2 heteromers in the endoplasmic reticulum of the hypothalamus diminished in SHR. In addition, α2δ‐1 C terminus peptide diminished inward rectification of AMPAR‐EPSCs and the inhibitory effect of IEM‐1460 on AMPAR‐EPSCs of PVN neurons in SHR. Thus, α2δ‐1 augments synaptic CP‐AMPARs by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension. These findings extend our understanding of the molecular basis of sustained sympathetic outflow in neurogenic hypertension.