α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly

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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“…In the spinal cord, increased α2δ-1 protein levels inhibit GluA1/GluA2 heteromeric assembly in the ER in neuropathic pain (Li et al, 2021).…”

Section: α2δ-1diminishesglua1/glua2heteromeric Assembly In the Er In ...mentioning

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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“…CP-AMPARs that lack the GluA2 subunit have a higher single-channel conductance than the CI-AMPARs which contain GluA2 [ 66 ]. For instance, a switch to CP-AMPAR (lacking GluA2 or containing unedited GluA2) increases neuronal excitability in the hypothalamus of hypertensive rats [ 67 ], in the hippocampus of mice with seizures [ 68 ], in spinal dorsal horn neurons of rats with inflammatory pain [ 69 , 70 ], and also in differentiated human MNs in amyotrophic lateral sclerosis model [ 71 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular Identification of Pro-Excitogenic Receptor and Channel Phenotypes of the Deafferented Lumbar Motoneurons in the Early Phase after SCT in Rats

Wojtaś

Skup

2022

IJMS

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Spasticity impacts the quality of life of patients suffering spinal cord injury and impedes the recovery of locomotion. At the cellular level, spasticity is considered to be primarily caused by the hyperexcitability of spinal α-motoneurons (MNs) within the spinal stretch reflex circuit. Here, we hypothesized that after a complete spinal cord transection in rats, fast adaptive molecular responses of lumbar MNs develop in return for the loss of inputs. We assumed that early loss of glutamatergic afferents changes the expression of glutamatergic AMPA and NMDA receptor subunits, which may be the forerunners of the developing spasticity of hindlimb muscles. To better understand its molecular underpinnings, concomitant expression of GABA and Glycinergic receptors and serotoninergic and noradrenergic receptors, which regulate the persistent inward currents crucial for sustained discharges in MNs, were examined together with voltage-gated ion channels and cation-chloride cotransporters. Using quantitative real-time PCR, we showed in the tracer-identified MNs innervating extensor and flexor muscles of the ankle joint multiple increases in transcripts coding for AMPAR and 5-HTR subunits, along with a profound decrease in GABAAR, GlyR subunits, and KCC2. Our study demonstrated that both MNs groups similarly adapt to a more excitable state, which may increase the occurrence of extensor and flexor muscle spasms.

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“…Glutamate NMDA receptor-mediated synaptic plasticity at the spinal cord level is crucially involved in central sensitization and neuropathic pain development. − α2δ-1 (encoded by the Cacna2d1 gene), previously known as a Ca 2+ channel subunit, is expressed in neurons in the DRG, spinal dorsal horn, and various brain regions. , α2δ-1 is the binding site of gabapentinoids, the first-line treatment for neuropathic pain conditions. Both traumatic nerve injury and paclitaxel treatment cause substantial and prolonged upregulation of α2δ-1 in the DRG. , Overexpression of α2δ-1 alone at the spinal cord level causes a long-lasting neuropathic pain-like phenotype. , Conversely, genetic knockout of Cacna2d1 profoundly attenuates neuropathic pain development after nerve injury or paclitaxel treatment. Recent studies revealed that upregulated α2δ-1 can form a protein complex with NMDA receptors to increase synaptic NMDA receptor trafficking in the spinal dorsal horn and that α2δ-1-bound NMDA receptors, not voltage-activated Ca 2+ channels, mediate the analgesic effect of gabapentinoids in various animal models of neuropathic pain. ,− Interestingly, pain hypersensitivity induced by JNJ-26481585, an HDAC inhibitor, in naive animals is reversed by gabapentin .…”

Section: Role Of Histone Modifications In Neuropathic Painmentioning

confidence: 99%

“…75,76 Overexpression of α2δ-1 alone at the spinal cord level causes a long-lasting neuropathic pain-like phenotype. 77,78 Conversely, genetic knockout of Cacna2d1 profoundly attenuates neuropathic pain development after nerve injury or paclitaxel treatment. Recent studies revealed that upregulated α2δ-1 can form a protein complex with NMDA receptors to increase synaptic NMDA receptor trafficking in the spinal dorsal horn and that α2δ-1-bound NMDA receptors, not voltage-activated Ca 2+ channels, mediate the analgesic effect of gabapentinoids in various animal models of neuropathic pain.…”

Section: Role Of Histone Modifications Inmentioning

confidence: 99%

Epigenetic Mechanisms of Neural Plasticity in Chronic Neuropathic Pain

Ghosh

Pan

2022

ACS Chem. Neurosci.

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Neuropathic pain is a challenging clinical problem and remains difficult to treat. Altered gene expression in peripheral sensory nerves and neurons due to nerve injury is well documented and contributes critically to the synaptic plasticity in the spinal cord and the initiation and maintenance of chronic pain. However, our understanding of the epigenetic mechanisms regulating the transcription of pro-nociceptive (e.g., NMDA receptors and α2δ-1) and antinociceptive (e.g., potassium channels and opioid and cannabinoid receptors) genes are still limited. In this review, we summarize recent studies determining the roles of histone modifications (including methylation, acetylation, and ubiquitination), DNA methylation, and noncoding RNAs in neuropathic pain development. We review the epigenetic writer, reader, and eraser proteins that participate in the transcriptional control of the expression of key ion channels and neurotransmitter receptors in the dorsal root ganglion after traumatic nerve injury, which is commonly used as a preclinical model of neuropathic pain. A better understanding of epigenetic reprogramming involved in the transition from acute to chronic pain could lead to the development of new treatments for neuropathic pain.

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α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly

Cited by 28 publications

References 48 publications

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

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

Molecular Identification of Pro-Excitogenic Receptor and Channel Phenotypes of the Deafferented Lumbar Motoneurons in the Early Phase after SCT in Rats

Epigenetic Mechanisms of Neural Plasticity in Chronic Neuropathic Pain

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α2δ-1 switches the phenotype of synaptic AMPA receptors by physically disrupting heteromeric subunit assembly

Cited by 28 publications

References 48 publications

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

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

Molecular Identification of Pro-Excitogenic Receptor and Channel Phenotypes of the Deafferented Lumbar Motoneurons in the Early Phase after SCT in Rats

Epigenetic Mechanisms of Neural Plasticity in Chronic Neuropathic Pain

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Product

Resources

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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

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