voltage-gated ion channels (VGICs), including Na+、Ca2 and K+Ion channels, in response to changes in membrane potential, selectively pass ions through the cell membrane, thus participating in neurotransmission, muscle contraction and hormone secretion and other physiological processes involving electrical signals.The abnormal function or disorder of VGICs is associated with a diversity of neurological, psychiatric, cardiovascular, and muscular diseases, and approximately 10% of FDA-approved drugs directly target VGICs. Understanding the structure-function relationships of VGICs is crucial to our understanding of their working mechanisms and their role in disease.
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 discusses how advances in single-particle cryo-electron microscopy have provided unprecedented structural insights into VGICs, particularly their interaction 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.
The field of animal electricity, also known as medical or bioelectricity, has been a major focus of physiology since L. Galvani observed in the late 18th century that a dead frog was electrocuted to cause muscle twitches.Over the next century and a half, the physical principles governing bioelectricity were gradually revealed. Na
+and K
+are the most abundant extracellular and intracellular cations in the human body, respectively,[Na
+]
ex/[Na]
+]
inabout 135-145 mM/~ 10 mM, [K
+]
ex/[K
+]
inbetween 3.5-5 mM/ 140-150 mM. Although the overall charge can be balanced with other asymmetrically distributed ions, such as Cl at higher concentrations in the extracellular environment
−but ions (such as K
+) The selective permeation establishes a transmembrane electric field, which lays the foundation for the emission of electrical signals.
Ca2 movement across the cell membrane is also a key event in the electrical signal：Ca
2 Not only is it another abundant cation, but due to its multifunctional protein-binding ability and relatively low basal concentration of around 100 nM in the cytoplasm, it acts as a second messenger in multiple signaling pathways.
In the postnatal animal, the electrical signal represented by the action potential is essential for almost all physiological and neural processes.Action potentials can propagate along myelinated axons at speeds of up to 120 m/s, enabling rapid responses to long-distance stimuli. Action potentials can be controlled by voltage-gated sodium or calcium (Navor Cav) channels and are initiated by voltage-gated potassium (Kv) Channel termination.As the name suggests, the opening and closing of these channels is controlled by changes in membrane voltage.
Structure and Classification of Voltage-Gated Ion Channels
Nav、Cavand KvThe channels constitute the basic members of the superfamily of voltage-gated ion channels (VGICs).Given their fundamental role in physiology, dysregulation or dysfunction of these pathways is associated with a wide range of neurological, cardiovascular, muscular and psychiatric disorders. Therefore, these channels are the target of a large number of drugs approved by the US Food and Drug Administration (FDA), including anti-arrhythmic drugs, anti-hypertensive drugs, analgesics, anti-epileptic drugs, and anti-depressants. Pharmacology, in turn, plays a key role in the identification and mechanistic study of VGICs, especially in the early stages of their exploration.
In addition, many natural products, including polypeptides and small molecule compounds, have been used to characterize VGICs.
The breakthroughs of the past decade have largely revolved around high-resolution structural resolution of many typical channels, enabled by the resolution revolution in single-particle cryo-electron microscopy (cryo-EM).These structures provide unprecedented clarity, advancing our understanding of the mechanisms of VGICs and how they interact with a variety of modulators, including natural ligands, pharmacological drugs, and auxiliary binding partners. An attempt is made in this review to provide an up-to-date summary of the structural underpinnings of selective ion permeation, voltage sensing, electromechanical coupling, and channel deactivation.
Then highlights the effects of drugs and toxins revealed by electron microscopy on the eukaryote Nav、Cavand KvRecent advances in the mechanism of action of channels.
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