Publications by authors named "Zhengyi Luo"

6 Publications

  • Page 1 of 1

Effects and mechanism of gating modifier spider toxins on the hERG channel.

Toxicon 2021 Jan 17;189:56-64. Epub 2020 Nov 17.

Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangdong Key Laboratory of Psychiatric Disorders, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China. Electronic address:

Jingzhaotoxin-I, -III, -IV, -XIII, and -35 (JZTX-I, -III, -IV, -XIII, and -35), gating modifier toxins isolated from the venom of the Chinese tarantula Chilobrachys Jingzhao, were reported to act on cardiac sodium channels and Kv channels. JZTX-I and JZTX-XIII inhibited the hERG channel with the IC value of 626.9 nM and 612.6 nM, respectively. JZTX-III, -IV, and -35 share high sequence similarity with JZTX-I and JZTX-XIII, but they showed much lower affinity on the hERG channel compared with JZTX-I and JZTX-XIII. The inhibitory potency of the above five toxins on the hERG channel was not in accordance with their affinity on the Nav1.5 and Kv2.1 channels, indicating that the bioactive surfaces of the five toxins interacting with hERG, Nav1.5 and Kv2.1 are at least in part different. Structure-function analysis of the gating modifier toxins suggested that the functional bioactive surface binding to the hERG channel consists of a conserved hydrophobic patch, surrounding acidic residues (Glu10 in JZTX-XIII, Glu11 in JZTX-I), and basic residues which may be different from residues binding to the Kv2.1 channel.
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http://dx.doi.org/10.1016/j.toxicon.2020.11.008DOI Listing
January 2021

Neuronal Inactivity Co-opts LTP Machinery to Drive Potassium Channel Splicing and Homeostatic Spike Widening.

Cell 2020 06 2;181(7):1547-1565.e15. Epub 2020 Jun 2.

Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman Medical Center, New York, NY 10016, USA; Center for Neural Science, New York University, New York, NY 10003, USA. Electronic address:

Homeostasis of neural firing properties is important in stabilizing neuronal circuitry, but how such plasticity might depend on alternative splicing is not known. Here we report that chronic inactivity homeostatically increases action potential duration by changing alternative splicing of BK channels; this requires nuclear export of the splicing factor Nova-2. Inactivity and Nova-2 relocation were connected by a novel synapto-nuclear signaling pathway that surprisingly invoked mechanisms akin to Hebbian plasticity: Ca-permeable AMPA receptor upregulation, L-type Ca channel activation, enhanced spine Ca transients, nuclear translocation of a CaM shuttle, and nuclear CaMKIV activation. These findings not only uncover commonalities between homeostatic and Hebbian plasticity but also connect homeostatic regulation of synaptic transmission and neuronal excitability. The signaling cascade provides a full-loop mechanism for a classic autoregulatory feedback loop proposed ∼25 years ago. Each element of the loop has been implicated previously in neuropsychiatric disease.
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http://dx.doi.org/10.1016/j.cell.2020.05.013DOI Listing
June 2020

Removal of hERG potassium channel affinity through introduction of an oxygen atom: Molecular insights from structure-activity relationships of strychnine and its analogs.

Toxicol Appl Pharmacol 2018 12 30;360:109-119. Epub 2018 Sep 30.

Key Laboratory of Mental Health of the Ministry of Education, Key Laboratory of Psychiatric Disorders of Guangdong Province, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China. Electronic address:

Nux vomica has been effectively used in Traditional Chinese Medicine. The processing of Nux vomica is necessary to reduce toxicity before it can be used in clinical practice. However, the mechanism for processing detoxification is unclear. hERG channels have been subjected to a routine test for compound cardiac toxicity in the drug development process. Therefore, we examined the effects and mechanisms of strychnine and brucine, two main ingredients of Nux vomica, and their N-oxides on hERG channels. Strychnine and brucine exhibited concentration-dependent inhibition of hERG channels with IC values of 25.9 μM and 44.18 μM, respectively. However, their nitrogen oxidative derivatives produced by processing of Nux vomica, strychnine N-oxide and brucine N-oxide, lost their activity on hERG channels. Compared to their parent compounds, only an oxygen atom was introduced in the nitrogen oxidative isoforms to compensate for the N - charge, suggesting that the protonated nitrogen is the key group for strychnine and brucine binding to hERG channel. Alanine-mutagenesis identified Y652 is the most important residue for strychnine and brucine binding to hERG channel. Y652A mutation increased the IC for strychnine and brucine by 21.64-fold and 29.78-fold that of WT I, respectively. Docking simulations suggested that the protonated nitrogen of strychnine and brucine formed a cation-π interaction with the aromatic ring of Y652. This study suggests that introduction of an oxygen to compensate for the N - charge could be a useful strategy for reducing hERG potency and increasing the safety margin of alkaloid-type compounds in drug development.
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http://dx.doi.org/10.1016/j.taap.2018.09.042DOI Listing
December 2018

Upregulation of phosphatase and tensin homolog is essential for the effect of 4-aminopyridine on A549/CDDP cells.

Mol Med Rep 2018 Apr 8;17(4):5996-6001. Epub 2018 Feb 8.

Institute of Respiratory Diseases, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China.

4-aminopyridine (4-AP), a voltage-gated potassium channel blocker, was revealed to possess pro‑apoptotic properties in various types of cancer cells. The present study aimed to explore the effect of 4‑AP on a cisplatin (DDP) resistant lung cancer cell line A549/CDDP and the underlying mechanism by which it had an effect. In the present study, an MTT assay and cell cycle analysis were used to determine that 4‑AP inhibited cell growth in vitro and a tumorigenesis assay in nude mice determined that 4‑AP also inhibited cell growth in vivo. 4‑AP induced cell apoptosis of A549/CDDP cells observed by electron microscopy and Annexin V‑APC/7‑ADD analysis. In addition, 4‑AP enhanced the sensitivity of A549/CDDP cells to DDP as revealed by an MTT assay. Mechanistically, 4‑AP upregulated the phosphatase and tensin homolog (PTEN) and modulated the phosphoinositide 3‑kinase/protein kinase B signaling pathway and its downstream cell cycle factors, including cyclin D1, cyclin‑dependent kinase 4 and p21, as well as apoptosis‑associated proteins B‑cell lymphoma 2, pro‑caspase 9, pro‑caspase 3, cleaved caspase 9 and cleaved caspase 3. The effects of 4‑AP on cell growth and apoptosis were reversed by PTEN silencing. In conclusion, the results indicated that 4‑AP inhibited cell growth, induced apoptosis and sensitized A549/CDDP cells to DDP via the upregulation of PTEN. 4‑AP may be a potential therapeutic agent for patients with DDP resistance.
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http://dx.doi.org/10.3892/mmr.2018.8585DOI Listing
April 2018

Nuclear BK channels regulate gene expression via the control of nuclear calcium signaling.

Nat Neurosci 2014 Aug 22;17(8):1055-63. Epub 2014 Jun 22.

1] State Key Laboratory of Organ Failure Research, Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. [2] Key Laboratory of Neuroplasticity of Guangdong Higher Education Institutes, Southern Medical University, Guangzhou, China.

Ion channels are essential for the regulation of neuronal functions. The significance of plasma membrane, mitochondrial, endoplasmic reticulum and lysosomal ion channels in the regulation of Ca(2+) is well established. In contrast, surprisingly little is known about the function of ion channels on the nuclear envelope (NE). Here we demonstrate the presence of functional large-conductance, calcium-activated potassium channels (BK channels) on the NE of rodent hippocampal neurons. Functionally, blockade of nuclear BK channels (nBK channels) induces NE-derived Ca(2+) release, nucleoplasmic Ca(2+) elevation and cyclic AMP response element binding protein (CREB)-dependent transcription. More importantly, blockade of nBK channels regulates nuclear Ca(2+)-sensitive gene expression and promotes dendritic arborization in a nuclear Ca(2+)-dependent manner. These results suggest that the nBK channel functions as a molecular link between neuronal activity and nuclear Ca(2+) to convey signals from synapse to nucleus and is a new modulator, operating at the NE, of synaptic activity-dependent neuronal functions.
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http://dx.doi.org/10.1038/nn.3744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4115017PMC
August 2014

Erbin interacts with TARP γ-2 for surface expression of AMPA receptors in cortical interneurons.

Nat Neurosci 2013 Mar 27;16(3):290-9. Epub 2013 Jan 27.

Institute of Developmental and Regenerative Biology, College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China.

Inhibitory neurons control the firing of glutamatergic neurons and synchronize brain activity. However, little is known about mechanisms of excitatory synapse formation in inhibitory neurons. Here we demonstrate that Erbin is specifically expressed in cortical inhibitory neurons. It localizes at excitatory synapses and regulates AMPA receptor (AMPAR) surface expression. Erbin mutation reduced mEPSCs and AMPAR currents specifically in parvalbumin (PV)-positive interneurons but not in pyramidal neurons. We found that the AMPAR auxiliary protein TARP γ-2 was specifically expressed in cortical interneurons. Erbin interacts with TARP γ-2 and is crucial for its stability. Deletion of the γ-2-interacting domain in Erbin attenuated surface AMPAR and excitatory transmission in PV-positive interneurons. Furthermore, we observed behavioral deficits in Erbin-null mice and in mice expressing an Erbin truncation mutant that is unable to interact with TARP γ-2. These observations demonstrate a crucial function for Erbin in AMPAR surface expression in cortical PV-positive interneurons and may contribute to a better understanding of psychiatric disorders.
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http://dx.doi.org/10.1038/nn.3320DOI Listing
March 2013