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Maybe change the whole field of ecology! Yan Ning's Team Cooperation Latest Cell Sub-journal

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Voltage-gated sodium (Nav) and calcium (Cav) The channel is responsible for the initiation of electrical signals. They have long been a target for the treatment of various diseases.Na from a variety of organismsvand CavThe increasing number of cryo-electron microscopy (cryo-EM) structures of different subtypes of channels requires a universal residue numbering system to establish structure-function relationships and facilitate rational drug design or optimization.

On August 15, 2024,Shenzhen Academy of Medical Sciences/Tsinghua University Yan Ning TeamCell Sub-JournalInCell Chemical Biology Online publication entitled"A versatile residue numbering scheme for Nav and Cav channels"'s research review paper, the studyA structure-based residue numbering scheme is proposed, centered on the most conserved residue on each functional fragment.

The article illustrates the universal number by example, focusing on the eukaryote Na.vand CavRepresentative drug binding sites of the channel. The article also extends the numbering scheme to compare different NavCommon disease mutations between subtypes.The application of the universal residue numbering scheme can directly understand the hot spots of pathogenic mutations and the key sites of drug binding, and will promote the targeting of Navand CavChannel drug discovery.

In addition,On August 5, 2024, the Shenzhen Academy of Medical Sciences/Tsinghua University Yan Ning teamNature Reviews Molecular Cell Biology(IF = 81) published online entitled"Structural biology and molecular pharmacology of voltage-gated ion channels"'s review article, which reviewsIt is discussed how advances in single-particle cryo-electron microscopy provideVGICsProvide unprecedented structural insights, especially their interactions with clinical and investigational drugs. This review provides a comprehensive overview of recent advances in the structural biology of VGICs, focusing on how prototype drugs and toxins modulate VGIC activity.This review explores how these structures elucidate the molecular basis of drug action, uncover new pharmacological sites, and provide key clues for future drug discovery.

Voltage-gated sodium (Nav) and calcium (Cav) Channels play a key role in electrical signals. NavChannels are indispensable for the excitation and transmission of action potentials. Calcium channels couple cell membrane depolarization to the influx of calcium ions, thereby regulating various physiological processes such as muscle contraction, secretion, neurotransmission, and gene expression.

Navand CavThe channels all belong to the voltage-gated ion channel (VGIC) superfamily. According to their sequence and structural similarity, the superfamily also includes Kvchannels, transient receptor potential (TRP) channels, and ryanodine receptors (RyRs).Initially, there was a lack of standardized nomenclature for the numerous isoforms of ion channels; descriptions were based on their localization, electrophysiological properties, and response to toxins and drugs. For example, Navchannels are classified as tetrodotoxin (TTX)-resistant and TTX-sensitive subtypes, whereas CavChannels are described as type-l for large and persistent currents, type-T for minute and transient currents, type-non-l and type-N for neurons, and so on.

In 1991, Chandy proposed a phylogenetic classification based on KvChannel numeric annotation nomenclature. A similar nomenclature was subsequently proposed for Navand CavChannel. This standardized nomenclature system, including Nav1.1-nav9 Na of 1.9vnomenclature of channel subtypes, and Cav1.1-Cav1.4、Cav2.1-Cav2.3 and Cav3.1-CavThe 10 Ca of 3.3vThe naming of the channel has been shown to facilitate scientific education, communication and cooperation.

Because of Navand CavThe basic significance of channels in physiology, their dysfunction or dysregulation is related to a variety of diseases.For example, NavThe 1.1 coding gene, SCN1A, contains hundreds of mutations associated with different forms of seizures, making it a vulnerable risk factor for epilepsy. Many Na + are found in patients with long QT syndrome type 3 (specific components of the LQT3, Q and T electrocardiogram)v1.5 gain-of-function (GOF) mutation, a major form of arrhythmia characterized by prolonged ventricular repolarization. On the other hand, NavHundreds of loss-of-function mutations in 1.5 genes are associated with Brugada syndrome. GOF or Nav1.7 nonsense mutations are associated with erythematous limb pain or congenital indifference to pain, respectively. Therefore, NavChannels have become targets for the treatment of arrhythmias, epilepsy and pain. CavThe same goes for the channel. CavBlockers, suchdihydropyridine(DHP) compounds, phenylalkylamines (PAAs) and benzothiazoles (BTZs), have been widely used for decades to treat cardiovascular and other diseases.Cav2.2 and Cav 3 channel is a target for the development of next generation painkillers.

A large number of literature and review articles well summarize the Navand CavResearch history, classification and (pathophysiology) of channels. Recently, researchers have alsovand CavAdvances in structural biology and structural pharmacology of channels are reviewed. In the preparation of these review articles, the researchers discovered a major inconvenience when it comes to the description of specific residues, that is, the same site has different residue numbers in different isoforms in different species and different splice variants.This difference may hinder the effective use of the large amount of available Navand Cavstructure to establish a structure-function relationship.

Inspired by the Ballesteros-Weinstein numbering scheme for G protein-coupled receptors (GPCRs), in which conserved residues are set as benchmarks, the researchers called for the Navand CavThe channel establishes a universal residue numbering scheme. In this article,The researchers will introduce the preliminary proposed numbering system and illustrate it with examples of drug binding sites and disease-causing mutations.

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South China University of Technology Gao Ping team work to reveal the role of ependymal-associated proteins in coordinating tumor immune evasion and cancer progression

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Wu Haitao of Nantong University and Chu Bo of Shandong University have shown that the development and survival of cerebellar Purkinje cells are regulated by iron death!

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