Focal Cerebral Ischemia and Reperfusion Induce Brain Injury Through α2δ-1–Bound NMDA Receptors

Journal of Neurochemistry

et al. 2018

Self Cite

Painful peripheral neuropathy is a severe and difficult‐to‐treat neurological complication associated with cancer chemotherapy. Although chemotherapeutic drugs such as paclitaxel are known to cause tonic activation of presynaptic NMDA receptors (NMDARs) to potentiate nociceptive input, the molecular mechanism involved in this effect is unclear. α2δ‐1, commonly known as a voltage‐activated calcium channel subunit, is a newly discovered NMDAR‐interacting protein and plays a critical role in NMDAR‐mediated synaptic plasticity. Here we show that paclitaxel treatment in rats increases the α2δ‐1 expression level in the dorsal root ganglion and spinal cord and the mRNA levels of GluN1, GluN2A, and GluN2B in the spinal cord. Paclitaxel treatment also potentiates the α2δ‐1–NMDAR interaction and synaptic trafficking in the spinal cord. Strikingly, inhibiting α2δ‐1 trafficking with pregabalin, disrupting the α2δ‐1–NMDAR interaction with an α2δ‐1 C‐terminus–interfering peptide, or α2δ‐1 genetic ablation fully reverses paclitaxel treatment‐induced presynaptic NMDAR‐mediated glutamate release from primary afferent terminals to spinal dorsal horn neurons. In addition, intrathecal injection of pregabalin or α2δ‐1 C‐terminus–interfering peptide and α2δ‐1 knockout in mice markedly attenuate paclitaxel‐induced pain hypersensitivity. Our findings indicate that α2δ‐1 is required for paclitaxel‐induced tonic activation of presynaptic NMDARs at the spinal cord level. Targeting α2δ‐1–bound NMDARs, not the physiological α2δ‐1–free NMDARs, may be a new strategy for treating chemotherapy‐induced neuropathic pain. Open science badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Section: Resultsmentioning

confidence: 70%

“…; Luo et al . ). Treatment with this α2δ‐1Tat peptide (1 μM for 30–60 min) completely normalized the increased baseline frequency of mEPSCs in lamina II neurons from paclitaxel‐treated rats ( n = 10 neurons) to the level seen in vehicle‐treated rats (Fig.…”

Section: Resultsmentioning

confidence: 97%

Increased α2δ‐1–NMDA receptor coupling potentiates glutamatergic input to spinal dorsal horn neurons in chemotherapy‐induced neuropathic pain

Journal of Neurochemistry

et al. 2018

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“…The C terminus of α2δ-1 is required for its interaction with NMDA receptors, 23 and a Tat (YGRKKRRQRRR)-fused 30-amino-acid peptide (VSGLNPSLWSIFGLQFILLWLVSGSRHYLW) effectively disrupts the α2δ-1-NMDA receptor interaction in vivo. 23,33 To determine the ability of α2δ-1Tat peptide to disrupt the α2δ-1-NMDA receptor interaction in the spinal cord of morphine-treated rats, we conducted coimmunoprecipitation analyses using membrane extracts of spinal cord tissue sections treated with 1 µM Tat-fused scrambled control peptide (FGLGWQPWSLSFYLVWSGLILSVLHLIRSN) or 1 µM α2δ-1Tat peptide for 30 min. Treatment with α2δ-1Tat peptide significantly reduced the level of the α2δ-1-GluN1 protein complex in the dorsal spinal cord, compared with that treated with the control peptide (P = 0.008, t (10) = 3.331, n = 6 rats/group; fig.…”

Section: Chronic Morphine Treatment Increases the Prevalence Of α2δ-1mentioning

confidence: 99%

α2δ-1–Bound N-Methyl-d-aspartate Receptors Mediate Morphine-induced Hyperalgesia and Analgesic Tolerance by Potentiating Glutamatergic Input in Rodents

Deng

et al. 2019

Anesthesiology

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Background: Chronic use of μ-opioid receptor agonists paradoxically causes both hyperalgesia and the loss of analgesic efficacy. Opioid treatment increases presynaptic N-methyl-d-aspartate receptor activity to potentiate nociceptive input to spinal dorsal horn neurons. However, the mechanism responsible for this opioid-induced activation of presynaptic N-methyl-d-aspartate receptors remains unclear. α2δ-1, formerly known as a calcium channel subunit, interacts with N-methyl-d-aspartate receptors and is primarily expressed at presynaptic terminals. This study tested the hypothesis that α2δ-1-bound N-methyl-d-aspartate receptors contribute to presynaptic N-methyl-d-aspartate receptor hyperactivity associated with opioid-induced hyperalgesia and analgesic tolerance.Methods: Rats (5 mg/kg) and wild-type and α2δ-1-knockout mice (10 mg/kg) were treated intraperitoneally with morphine twice/day for 8 consecutive days, and nociceptive thresholds were examined. Presynaptic N-methyl-d-aspartate receptor activity was recorded in spinal cord slices. Coimmunoprecipitation was performed to examine protein-protein interactions.Results: Chronic morphine treatment in rats increased α2δ-1 protein amounts in the dorsal root ganglion and spinal cord. Chronic morphine exposure also increased the physical interaction between α2δ-1 and N-methyl-d-aspartate receptors by 1.5 ± 0.3 fold (means ± SD, P = 0.009, n = 6) and the prevalence of α2δ-1-bound N-methyl-d-aspartate receptors at spinal cord synapses. Inhibiting α2δ-1 with gabapentin or genetic knockout of α2δ-1 abolished the increase in presynaptic N-methyl-d-aspartate receptor activity in the spinal dorsal horn induced by morphine treatment. Furthermore, uncoupling the α2δ-1-Nmethyl-d-aspartate receptor interaction with an α2δ-1 C terminus-interfering peptide fully reversed morphine-induced tonic activation of N-methyl-d-aspartate receptors at the central terminal of primary afferents. Finally, intraperitoneal injection of gabapentin or intrathecal injection of an α2δ-1 C terminus-interfering peptide or α2δ-1 genetic knockout abolished the mechanical and thermal hyperalgesia induced by chronic morphine exposure and largely preserved morphine's analgesic effect during 8 days of morphine treatment.conclusions: α2δ-1-Bound N-methyl-d-aspartate receptors contribute to opioid-induced hyperalgesia and tolerance by augmenting presynaptic N-methyl-d-aspartate receptor expression and activity at the spinal cord level. What We Already Know about This Topic• Presynaptic N-methyl-d-aspartate receptors contribute to opioid tolerance and hyperalgesia as well as neuropathic pain • The α2δ-1 protein subunit enhances presynaptic N-methyl-daspartate receptor activity What This Article Tells Us That Is New• Using mouse and rat models, it was demonstrated that α2δ-1 is essential for the increase in presynaptic N-methyl-d-aspartate receptor activity seen during chronic morphine exposure • Inhibiting α2δ-1 activity using gabapentin or genetically deleting the gene coding for α2δ-1 results in diminished o...

“…We used a 30-amino acid peptide (VSGLNPSLWSIFGLQFILLWLVSGSRHYLW) mimick-ing the C-terminal domain of ␣2␦-1, which specifically diminishes the ␣2␦-1-NMDAR interaction (17). Because ␣2␦-1 primarily promotes forward trafficking of intracellular ␣2␦-1bound NMDARs, we fused the peptide to the cell-penetrating peptide Tat (YGRKKRRQRRR), generating ␣2␦-1Tat peptide to disrupt the interaction between ␣2␦-1 and NMDARs (17,35). We have shown that ␣2␦-1Tat peptide has no effect on VGCC currents and the Cav␣1-␣2␦-1 interaction (17,35).…”

Section: ␣2␦-1 Is Critically Required For Tbs-induced Corticostriatalmentioning

confidence: 99%

The α2δ-1–NMDA receptor coupling is essential for corticostriatal long-term potentiation and is involved in learning and memory

Zhou

Journal of Biological Chemistry

et al. 2018

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The striatum receives extensive cortical input and plays a prominent role in motor learning and habit formation. Glutamate N‐methyl‐Daspartate (NMDA) receptor (NMDAR)‐mediated long‐term potentiation (LTP) is a major synaptic plasticity involved in learning and memory. However, the molecular mechanism underlying NMDAR plasticity in corticostriatal LTP is unclear. Here, we show that theta‐burst stimulation (TBS) consistently induced corticostriatal LTP and increased the coincident presynaptic and postsynaptic NMDAR activity of medium spiny neurons. We also found that α2δ‐1 (previously known as a subunit of voltage‐gated calcium channels; encoded by the Cacna2d1 gene) physically interacted with NMDARs in the striatum of mice and humans, indicating that this crosstalk is conserved across species. Strikingly, inhibiting α2δ‐1 trafficking with gabapentin or disrupting the α2δ‐1–NMDAR interaction with an α2δ‐1 C‐terminus–interfering peptide abolished TBS‐induced LTP. In Cacna2d1‐knockout mice, TBS failed to induce corticostriatal LTP and the associated increases in presynaptic and postsynaptic NMDAR activities. Moreover, systemic gabapentin treatment, microinjection of α2δ‐1 C‐terminus–interfering peptide into the dorsomedial striatum, or Cacna2d1 ablation impaired the alternation T‐maze task and rotarod performance in mice. Our findings indicate that the interaction between α2δ‐1 and NMDARs is of high physiological relevance and that a TBS‐induced switch from α2δ‐1–free to α2δ‐1–bound NMDARs is critically involved in corticostriatal LTP and LTP‐associated learning and memory. Gabapentinoids may adversely affect cognitive function by targeting α2δ‐1–NMDAR complexes. Support or Funding Information Human brain tissues were obtained from the Harvard Brain Tissue Resources Center, a NeuroBioBank Repository funded by the National Institutes of Health. This work was supported by the National Institutes of Health (GM120844 and NS101880 to H.‐L.P.) and by the N.G. and Helen T. Hawkins Endowment. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.