Group III metabotropic glutamate receptors regulate hypothalamic presympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension

Zhou, Jingjing; Pachuau, Judith; Li, De Pei; Pan, Hui

doi:10.1016/j.neuropharm.2020.108159

Cited by 9 publications

(7 citation statements)

References 41 publications

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“…Spinally projecting and RVLM-projecting PVN neurons were retrogradely labeled as described previously. 30,38 The firing activity of labeled PVN neurons was recorded using a perforated whole-cell method, as we described previously. 41,42 The miniature excitatory postsynaptic currents (mEPSCs) were recorded at a holding potential of –60 mV.…”

Section: Methodsmentioning

confidence: 99%

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

Zhou

Shao

Pan

2022

Circulation Research

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Rationale: Hypertension is a common and serious adverse effect of calcineurin inhibitors, including cyclosporine and tacrolimus (FK506). Although increased sympathetic nerve discharges are associated with calcineurin inhibitor–induced hypertension, the sources of excess sympathetic outflow and underlying mechanisms remain elusive. Calcineurin (protein phosphatase-2B) is broadly expressed in the brain, including the paraventricular nuclear (PVN) of the hypothalamus, which is critically involved in regulating sympathetic vasomotor tone. Objective: We determined whether prolonged treatment with the calcineurin inhibitor causes elevated sympathetic output and persistent hypertension by potentiating synaptic N-methyl-D-aspartate (NMDA) receptor activity in the PVN. Methods and Results: Telemetry recordings showed that systemic administration of FK506 (3 mg/kg per day) for 14 days caused a gradual and profound increase in arterial blood pressure in rats, which lasted at least 7 days after discontinuing FK506 treatment. Correspondingly, systemic treatment with FK506 markedly reduced calcineurin activity in the PVN and circumventricular organs, but not rostral ventrolateral medulla, and increased the phosphorylation level and synaptic trafficking of NMDA receptors in the PVN. Immunocytochemistry labeling showed that calcineurin was expressed in presympathetic neurons in the PVN. Whole-cell patch-clamp recordings in brain slices revealed that treatment with FK506 increased baseline firing activity of PVN presympathetic neurons; this increase was blocked by the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist. Also, treatment with FK506 markedly increased presynaptic and postsynaptic NMDA receptor activity of PVN presympathetic neurons. Furthermore, microinjection of the NMDA or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist into the PVN of anesthetized rats preferentially attenuated renal sympathetic nerve discharges and blood pressure elevated by FK506 treatment. In addition, systemic administration of memantine, a clinically used NMDA receptor antagonist, effectively attenuated FK506 treatment–induced hypertension in conscious rats. Conclusions: Our findings reveal that normal calcineurin activity in the PVN constitutively restricts sympathetic vasomotor tone via suppressing NMDA receptor activity, which may be targeted for treating calcineurin inhibitor–induced hypertension.

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Section: Methodsmentioning

confidence: 99%

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

Zhou

Shao

Pan

2022

Circulation Research

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“…Spinally projecting PVN neurons were retrogradely labeled as described previously (Zhou et al, 2020; Li et al, 2012). Rats were anesthetized with 3% isoflurane, and dorsal laminectomy was performed to expose spinal cord at T2–T4 levels.…”

Section: Methodsmentioning

confidence: 99%

“…Animals were purchased from Harlan Laboratories (Envigo) and housed on a 12‐h light/dark cycle with free access to food and water. Before the final experiments, arterial blood pressure in each animal was measured using a tail‐cuff method to ensure that the level of systemic blood pressure matches that of SHR and WKY (Zhou et al, 2020; Li & Pan, 2007). All experimental procedures and protocols were approved (Approval #919‐RN03) by the Institutional Animal Care and Use Committee of the MD Anderson Cancer Center and conformed to the National Institutes of Health guidelines on the ethical use of animals.…”

Section: Methodsmentioning

confidence: 99%

α2δ‐1 protein promotes synaptic expression of Ca²⁺ permeable–AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension

Zhou

Shao

Chen

et al. 2022

Journal of Neurochemistry

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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 AMPARmediated 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.

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“…GABA and glutamate are the central nervous system's primary inhibitory and excitatory neurotransmitters [28][29][30]. In-vivo [17,[31][32][33][34][35] and in-vitro [33][34][35][36][37][38] electrophysiological data show that an imbalance of GABAergic and glutaminergic activity within the PVN occurs in neurogenic hypertension observed in the SHR.…”

Section: Introductionmentioning

confidence: 99%

Inactivation of the paraventricular nucleus attenuates the cardiogenic sympathetic afferent reflex in the spontaneously hypertensive rat

Zahner,

Brown,

Chandley

2023

Journal of Hypertension

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Background: Myocardial ischemia causes the release of bradykinin, which stimulates cardiac afferents, causing sympathetic excitation and chest pain. Glutamatergic activation of the paraventricular hypothalamic nucleus (PVN) in the spontaneously hypertensive rat (SHR) drives elevated basal sympathetic activity. Thus, we tested the hypothesis that inactivation of the PVN attenuates the elevated reflex response to epicardial bradykinin in the SHR and that ionotropic PVN glutamate receptors mediate the elevated reflex. Methods: We recorded the arterial pressure and renal sympathetic nerve activity (RSNA) response to epicardial bradykinin application in anesthetized SHR and Wistar Kyoto (WKY) rats before and after PVN microinjection of GABAA agonist muscimol or ionotropic glutamate receptor antagonist kynurenic acid. Results: Muscimol significantly decreased the arterial pressure response to bradykinin from 180.4 ± 5.8 to 119.5 ± 6.9 mmHg in the SHR and from 111.8 ± 7.0 to 84.2 ± 8.3 mmHg in the WKY and the RSNA response from 186.2 ± 7.1 to 142.7 ± 7.3% of baseline in the SHR and from 201.0 ± 11.5 to 160.2 ± 9.3% of baseline in the WKY. Kynurenic acid significantly decreased the arterial pressure response in the SHR from 164.5 ± 5.0 to 126.2 ± 7.7 mmHg and the RSNA response from 189.9 ± 13.7to 168.5 ± 12.7% of baseline but had no effect in the WKY. Conclusion: These results suggest that tonic PVN activity is critical for the full manifestation of the CSAR in both the WKY and SHR. Glutamatergic PVN activity contributes to the augmented CSAR observed in the SHR.

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Group III metabotropic glutamate receptors regulate hypothalamic presympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension

Cited by 9 publications

References 41 publications

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

α2δ‐1 protein promotes synaptic expression of Ca²⁺ permeable–AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension

Inactivation of the paraventricular nucleus attenuates the cardiogenic sympathetic afferent reflex in the spontaneously hypertensive rat

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Group III metabotropic glutamate receptors regulate hypothalamic presympathetic neurons through opposing presynaptic and postsynaptic actions in hypertension

Cited by 9 publications

References 41 publications

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

Calcineurin Controls Hypothalamic NMDA Receptor Activity and Sympathetic Outflow

α2δ‐1 protein promotes synaptic expression of Ca2+ permeable–AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension

Inactivation of the paraventricular nucleus attenuates the cardiogenic sympathetic afferent reflex in the spontaneously hypertensive rat

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α2δ‐1 protein promotes synaptic expression of Ca²⁺ permeable–AMPA receptors by inhibiting GluA1/GluA2 heteromeric assembly in the hypothalamus in hypertension