The cross channel activities of spider neurotoxin huwentoxin-I on rat dorsal root ganglion neurons.

Structure-function relationship of new peptides activating human Nav1.1.

The Kv4.3 channel is featured of fast N-type inactivation and also undergoes a slow C-type inactivation. The gain-of-function mutations of Kv4.3 channels cause an inherited disease called Brugada syndrome characterized by a shortened duration of cardiac action potential repolarization and ventricular arrhythmia. The sulfonylurea drug gliquidone, an ATP-dependent K+ channel antagonist, is widely used for the treatment of type 2 diabetes. Here, we report a novel role of gliquidone in inhibiting Kv4.3 and Kv4.3/KChIP2 channels that encode the cardiac Ito currents responsible for the initial phase of action potential repolarization. Gliquidone results in concentration-dependent inhibition of both Kv4.3 and Kv4.3/KChIP2 fast or steady-state inactivation currents with an IC50 of approximately 8 μM. Gliquidone also accelerates Kv4.3 channel inactivation and shifts the steady-state activation to a more depolarizing direction. Site-directed mutagenesis and molecular docking reveal that the residues S301 in the S4 and Y312A, L321A in the S4-S5 linker are critical for gliquidone-mediated inhibition of Kv4.3 currents, as mutating those residues to alanine significantly reduces the potency for gliquidone-mediated inhibition. Furthermore, gliquidone also inhibits a gain-of-function Kv4.3 V392I mutant identified in BrS patients in voltage- and concentration-dependent manner. Taken together, our findings demonstrate that gliquidone inhibits Kv4.3 channels by acting on the residues in the S4 and the S4-S5 linker. Therefore, gliquidone may hold repurposing potential for the therapy of Brugada syndrome. Significance Statement We describe a novel role of gliquidone in inhibiting cardiac Kv4.3 currents and the channel gain-of-function mutation identified from patients with Brugada syndrome, suggesting its repurposing potential for therapy for the heart disease.

Inhibition of cardiac Kv4.3/KChIP2 channels by a sulfonylurea drug gliquidone

JZTX-V, a Sodium Channel Inhibitor, Exhibits Excellent Analgesic Effects in Mouse Models

ABSTRACT Latroeggtoxin‐VI (LETX‐VI), a peptide toxin discovered from the eggs of spider Latrodectus tredecimguttatus , was previously shown to promote the synthesis and release of dopamine in rat pheochromocytoma (PC12) cells, showing potential applications in the neurobiology and medicine. To further understand the structure and properties of LETX‐VI, the key residues were identified and their roles in the structure, function, and stability of LETX‐VI were analyzed in the present work. Based on the protein molecular docking, our previous work, and the relevant literature, the potential key residues of LETX‐VI were selected and identified by alanine‐scanning mutagenesis. The wild‐type LETX‐VI and its 13 mutants, including a double mutant, were prepared by gene cloning and heterologous expression in Escherichia coli , followed by activity, structure, and stability determination. The results demonstrated that the activity of the mutants K25A, R35A, K40A/R41A, and L45A, particularly R35A, to promote dopamine release from PC12 cells was significantly decreased compared with that of the wild‐type LETX‐VI, indicating that these mutated residues are the key residues. Circular dichroism (CD) analysis showed that the secondary structure of these mutants was not obviously different from that of wild‐type LETX‐VI, suggesting that mutation‐caused decrease in the activity of LETX‐VI is due to the changes in the binding site on the molecule surface, rather than the abnormal alternation of the molecular conformation of LETX‐VI. Acetonitrile (ACN) did not obviously influence the activity of LETX‐VI; however, 0.1% trifluoroacetic acid (TFA) treatment for 2 h significantly reduced its activity. Treatment with weakly acidic and basic buffers (pH ≥ 6.6) for 12 h was favorable for LETX‐VI and R35A to exert their activity. Higher temperatures (&gt;37°C) decreased the activity of both wild‐type LETX‐VI and R35A. In conclusion, K25, R35, K40, R41, and L45 particularly R35 are the important functional site residues; during experiments, care should be taken to avoid the adverse influence of strong acid and high temperature on LETX‐VI. These observations have enhanced our understanding of the structure and properties of LETX‐VI and provided references for the subsequent modification of structure and function of LETX‐VI. 

Structure–Function Relationship and Stability of Latroeggtoxin‐<scp>VI</scp>: A Proteinaceous Toxin From the Eggs of <scp>Latrodectus tredecimguttatus</scp>

ABSTRACT JZTX-V is a toxin isolated from the venom of the Chinese spider Chilobrachys jingzhao. Previous studies had shown that JZTX-V could inhibit the transient outward potassium current of Kv4.2 and Kv4.3 expressed in Xenopus oocytes but had no effects on Kv1.2–1.4. However, the underlying action mechanism of JZTX-V on Kv4.3 remains unclear. In our study, JZTX-V could inhibit not only transient outward potassium currents evoked in small-sized DRG neurons but also Kv4.3-encoded currents expressed in HEK293T cells in the concentration and voltage dependence. The half maximal inhibitory concentration of JZTX-V on Kv4.3 was 9.6 ± 1.2 nM. In addition, the time course for JZTX-V inhibition and release of inhibition after washout were 15.8 ± 1.54 s and 58.8 ± 4.35 s. Electrophysiological assays indicated that 25 nM JZTX-V could shift significantly the voltage dependence of steady-state activation and steady-state inactivation to depolarization. Meanwhile, 25 nM JZTX-V decreased markedly the time constant of activation and inactivation but had no effect on the time constant of recovery from inactivation. To study the molecular determinants of Kv4.3, we performed alanine scanning on a conserved motif of Kv4.3 and assayed the affinity between mutants and JZTX-V. The results not only showed that I273, L275, V283, and F287 were molecular determinants in the conserved motif of Kv4.3 for interacting with JZTX-V but also speculated the underlying action mechanism that the hydrophobic interaction and steric effects played key roles in the binding of JZTX-V with Kv4.3. In summary, our studies have laid a scientific theoretical foundation for further research on the interaction mechanism between JZTX-V and Kv4.3.

https://www.tandfonline.com/doi/pdf/10.1080/19336950.2022.2053420?needAccess=true

Effects of JZTX-V on the wild type Kv4.3 Expressed in HEK293T and Molecular Determinants in the Voltage-sensing Domains of Kv4.3 Interacting with JZTX-V

Chemical synthesis and physiological activity analysis of K3A-HWTX-I: A mutant of huwentoxin-I

Pituitary gland is critical for the control growth and development in animals. D-galactose induced aging model has been widely used to study the aging mechanism and the screening of drugs. Herein,two dimensional gel electrophoresis ( 2-DE) followed by mass spectrometry( MS) was performed to exemine proteome differences in pituitary gland between control and D-galactose treated mice. Thereafter,pituitary glands were isolated from controlled and D-galactose treated mice,and pituitary gland proteins were subjected to 2-DE based comparative proteomic analysis ( n = 8,4 gels in each group) ,which revealed 46 differentially expressed proteins ( > 2 fold) . Among them,32 were identified successfully by mass spectrometry. The results implicated that the altered proteins were mainly involved in glucose metabolism pathway and might contribute to mitochondrial dysfunction. Our data may help to better understanding of molecular mechanisms of pituitary dysfunction in aging mice induced by Dgalactose.

Differential Proteomic Analysis of Pituitary Gland from D-galactose Induced Aging Mice

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Effects of JZTX-V on the wild type Kv4.3 Expressed in HEK293T and Molecular Determinants in the Voltage-sensing Domains of Kv4.3 Interacting with JZTX-V

Chemical synthesis and physiological activity analysis of K3A-HWTX-I: A mutant of huwentoxin-I

Differential Proteomic Analysis of Pituitary Gland from D-galactose Induced Aging Mice