Brain α2δ-1–Bound NMDA Receptors Drive Calcineurin Inhibitor–Induced Hypertension

Jing-Jing Zhou

Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston.

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Jian-Ying Shao

Jian-Ying Shao

Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston.

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Shao-Rui Chen

Shao-Rui Chen

Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston.

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and

Hui-Lin Pan

Hui-Lin Pan

Correspondence to: Hui-Lin Pan, MD, PhD, Department of Anesthesiology and Perioperative Medicine, Unit 110, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030. Email

E-mail Address: [email protected]

https://orcid.org/0000-0001-8444-3770

Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston.

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Originally published22 Aug 2023https://doi.org/10.1161/CIRCRESAHA.123.322562Circulation Research. 2023;133:611–627

Abstract

BACKGROUND:

Calcineurin is highly enriched in immune T cells and the nervous system. Calcineurin inhibitors, including cyclosporine and tacrolimus (FK506), are the cornerstone of immunosuppressive regimens for preserving transplanted organs and tissues. However, these drugs often cause persistent hypertension owing to excess sympathetic outflow, which is maintained by N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory input to the hypothalamic paraventricular nucleus (PVN). It is unclear how calcineurin inhibitors increase NMDAR activity in the PVN to augment sympathetic vasomotor activity. α2δ-1 (encoded by the Cacna2d1 gene), known colloquially as a calcium channel subunit, is a newly discovered NMDAR-interacting protein. In this study, we determined whether α2δ-1 plays a role in calcineurin inhibitor–induced synaptic NMDAR hyperactivity in the PVN and hypertension development.

METHODS:

Immunoblotting and coimmunoprecipitation assays were used to quantify synaptic protein levels and the physical interaction between GluN1 (the obligatory NMDAR subunit) and α2δ-1. Whole-cell patch-clamp recordings of retrogradely labeled, spinally projecting PVN were conducted in perfused brain slices to measure presynaptic and postsynaptic NMDAR activity. Radio-telemetry was implanted in rodents to continuously record arterial blood pressure in conscious states.

RESULTS:

Prolonged treatment with FK506 in rats significantly increased protein levels of α2δ-1, GluN1, and the α2δ-1-GluN1 complex in PVN synaptosomes. These effects were blocked by inhibiting α2δ-1 with gabapentin or interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C-terminus peptide. Treatment with FK506 potentiated the activity of presynaptic and postsynaptic NMDARs in spinally projecting PVN neurons; such effects were abolished by gabapentin, Cacna2d1 knockout, or α2δ-1 C-terminus peptide. Furthermore, microinjection of α2δ-1 C-terminus peptide into the PVN diminished renal sympathetic nerve discharges and arterial blood pressure that had been increased by FK506 treatment. Remarkably, concurrent administration of gabapentin prevented the development of FK506-induced hypertension in rats. Additionally, FK506 treatment induced sustained hypertension in wild-type mice but not in Cacna2d1 knockout mice.

CONCLUSIONS:

α2δ-1 is essential for calcineurin inhibitor–induced increases in synaptic NMDAR activity in PVN presympathetic neurons and sympathetic outflow. Thus, α2δ-1 and α2δ-1-bound NMDARs represent new targets for treating calcineurin inhibitor–induced hypertension. Gabapentinoids (gabapentin and pregabalin) could be repurposed for treating calcineurin inhibitor–induced neurogenic hypertension.

Footnotes

For Sources of Funding and Disclosures, see page 625.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCRESAHA.123.322562.

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Circulation Research, volume 133 issue 7 cover

September 15, 2023
Vol 133, Issue 7

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https://doi.org/10.1161/CIRCRESAHA.123.322562

PMID: 37605933

Manuscript receivedJanuary 18, 2023
Manuscript acceptedAugust 9, 2023
Originally publishedAugust 22, 2023
Manuscript revisedAugust 8, 2023

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Brain α2δ-1–Bound NMDA Receptors Drive Calcineurin Inhibitor–Induced Hypertension