Mechanism of agonist-induced activation of the human itch receptor MRGPRX1.

Mas-related G-protein-coupled receptors X1-X4 (MRGPRX1-X4) are 4 primate-specific receptors that are recently reported to be responsible for many biological processes, including itch sensation, pain transmission, and inflammatory reactions. MRGPRX1 is the first identified human MRGPR, and its expression is restricted to primary sensory neurons. Due to its dual roles in itch and pain signaling pathways, MRGPRX1 has been regarded as a promising target for itch remission and pain inhibition. Here, we reported a cryo-electron microscopy (cryo-EM) structure of Gq-coupled MRGPRX1 in complex with a synthetic agonist compound 16 in an active conformation at an overall resolution of 3.0 Å via a NanoBiT tethering strategy. Compound 16 is a new pain-relieving compound with high potency and selectivity to MRGPRX1 over other MRGPRXs and opioid receptor. MRGPRX1 was revealed to share common structural features of the Gq-mediated receptor activation mechanism of MRGPRX family members, but the variable residues in orthosteric pocket of MRGPRX1 exhibit the unique agonist recognition pattern, potentially facilitating to design MRGPRX1-specific modulators. Together with receptor activation and itch behavior evaluation assays, our study provides a structural snapshot to modify therapeutic molecules for itch relieving and analgesia targeting MRGPRX1.

Identification of an arthropod molecular target for plant-derived natural repellents.

Arthropods maintain ecosystem balance while also contributing to the spread of disease. Plant-derived natural repellents represent an ecological method of pest control, but their direct molecular targets in arthropods remain to be further elucidated. Occupying a critical phylogenetic niche in arthropod evolution, scorpions retain an ancestral genetic profile. Here, using a behavior-guided screening of the Mesobuthus martensii genome, we identified a scorpion transient receptor potential (sTRP1) channel that senses Cymbopogon-derived natural repellents, while remaining insensitive to the synthetic chemical pesticide DEET. Scrutinizing orthologs of sTRP1 in Drosophila melanogaster, we further demonstrated dTRPγ ion channel as a chemosensory receptor of natural repellents to mediate avoidance behavior. This study sheds light on arthropod molecular targets of natural repellents, exemplifying the arthropod­plant adaptation. It should also help the rational design of insect control strategy and in conserving biodiversity.

Impaired fertility in 4930590J08Rik mutant male mice is associated with defective sperm energy metabolism.

Testis-specifically expressed genes are important for male reproduction according to their unique expression patterns. However, the functions of most of these genes in reproduction are unclear. Here, we showed that mouse 4930590J08Rik was a testis-specifically expressed gene. 4930590J08Rik knockout mice exhibited a delay in the first wave of spermatogenesis and a reduction of cauda epididymal sperm. Furthermore, knockout spermatozoa exhibited defective acrosome reactions and decreased progressive motility, which led to impaired in vivo fertilization. Transcriptome analysis of testes revealed that most of the differentially expressed genes in knockout testes were associated with metabolic processes. 4930590J08Rik knockout sperm exhibited oxidative phosphorylation deficiency and were highly dependent on increased anaerobic glycolysis to compensate for ATP demands. Taken together, the 4930590J08Rik-disrupted mouse partially mimics the phenotypes of human asthenospermia and oligozoospermia, which provides a new model for further understanding the pathogenesis of idiopathic male infertility.

Scorpion venom peptides: Molecular diversity, structural characteristics, and therapeutic use from channelopathies to viral infections and cancers.

Animal venom is an important evolutionary innovation in nature. As one of the most representative animal venoms, scorpion venom contains an extremely diverse set of bioactive peptides. Scorpion venom peptides not only are 'poisons' that immobilize, paralyze, kill, or dissolve preys but also become important candidates for drug development and design. Here, the review focuses on the molecular diversity of scorpion venom peptides, their typical structural characteristics, and their multiple therapeutic or pharmaceutical applications in channelopathies, viral infections and cancers. Especially, the group of scorpion toxin TRPTx targeting transient receptor potential (TRP) channels is systematically summarized and worthy of attention because TRP channels play a crucial role in the regulation of homeostasis and the occurrence of diseases in human. We also further establish the potential relationship between the molecular characteristics and functional applications of scorpion venom peptides to provide a research basis for modern drug development and clinical utilization of scorpion venom resources.

The tick saliva peptide HIDfsin2 promotes the tick-borne virus SFTSV replication in vitro by enhancing p38 signal pathway.

Pathogens co-evolved with ticks to facilitate blood collection and pathogen transmission. Although tick saliva was recently found to be rich in bioactive peptides, it is still elusive which saliva peptide promotes virus transmission and which pathways are invovled. Here, we used a saliva peptide HIDfsin2 and a severe fever with thrombocytopenia syndrome virus (SFTSV) both carried by the tick Haemaphysalis longicornis to elucidate the relationship between tick saliva components and tick-borne viruses. HIDfsin2 was found to promote the replication of SFTSV in a dose-dependent manner in vitro. HIDfsin2 was further revealed to MKK3/6-dependently magnify the activation of p38 MAPK. The overexpression, knockdown and phosphorylation site mutation of p38α indicated that p38 MAPK activation facilitated SFTSV infection in A549 cells. Moreover, the blockade of p38 MAPK activation significantly suppressed SFTSV replication. Differently, HIDfsin2 or pharmacological inhibition of p38 MAPK activation had no effect on a mosquito-borne Zika virus (ZIKV). All these results showed that HIDfsin2 specifically promoted SFTSV replication through the MKK3/6-dependent enhancement of p38 MAPK activation. Our study provides a new perspective on the transmission of tick-borne viruses under natural conditions, and supports that the blockade of p38 MAPK activation can be a promising strategy against the mortal tick-borne virus SFTSV.

A study on the correlation of the asymmetric regulation between the periaqueductal gray and the bilateral trigeminal nucleus caudalis in migraine male rats.

BACKGROUND: The study was designed to explore the correlation of the asymmetric regulation between periaqueductal gray (PAG) and bilateral trigeminal nucleus caudalis (TNC) in migraine rats through studying the changes of metabolites in pain regulatory pathway of acute migraine attack. METHODS: Thirty male Sprague-Dawley (SD) rats were randomly divided into three groups: blank, control, model groups. Then, blank group was intraperitoneally injected with ultrapure water, while control group injected with saline and model group injected with Glyceryl Trinitrate (GTN). Two hours later, PAG and bilateral TNC were removed respectively, and metabolite concentrations of PAG, Left-TNC, Right-TNC were obtained. Lastly, the differences of metabolite among three brain tissues were compared. RESULTS: The relative concentrations of rNAA, rGlu, rGln, rTau, rMI in PAG or bilateral TNC had interaction effects between groups and sites. The concentration of rLac of three brain tissues increased in migraine rats, however, the rLac of LTNC and RTNC increased more than that of PAG. Besides, the concentrations of rNAA and rGln increased in RTNC, while rGABA decreased in RTNC. CONCLUSIONS: There is correlation between PAG, LTNC and RTNC in regulation of pain during acute migraine attack, and the regulation of LTNC and RTNC on pain is asymmetric.

Mechanisms Underlying the Inhibition of KV1.3 Channel by Scorpion Toxin ImKTX58.

Voltage-gated KV1.3 channel has been reported to be a drug target for the treatment of autoimmune diseases, and specific inhibitors of Kv1.3 are potential therapeutic drugs for multiple diseases. The scorpions could produce various bioactive peptides that could inhibit KV1.3 channel. Here, we identified a new scorpion toxin polypeptide gene ImKTX58 from the venom gland cDNA library of the Chinese scorpion Isometrus maculatus Sequence alignment revealed high similarities between ImKTX58 mature peptide and previously reported KV1.3 channel blockers-LmKTX10 and ImKTX88-suggesting that ImKTX58 peptide might also be a KV1.3 channel blocker. By using electrophysiological recordings, we showed that recombinant ImKTX58 prepared by genetic engineering technologies had a highly selective inhibiting effect on KV1.3 channel. Further alanine scanning mutagenesis and computer simulation identified four amino acid residues in ImKTX58 peptide as key binding sites to KV1.3 channel by forming hydrogen bonds, salt bonds, and hydrophobic interactions. Among these four residues, 28th lysine of the ImKTX58 mature peptide was found to be the most critical amino acid residue for blocking KV1.3 channel. SIGNIFICANCE STATEMENT: In this study, we discovered a scorpion toxin gene ImKTX58 that has not been reported before in Hainan Isometrus maculatus and successfully used the prokaryotic expression system to express and purify the polypeptides encoded by this gene. Electrophysiological experiments on ImKTX58 showed that ImKTX58 has a highly selective blocking effect on KV1.3 channel over Kv1.1, Kv1.2, Kv1.5, SK2, SK3, and BK channels. These findings provide a theoretical basis for designing highly effective KV1.3 blockers to treat autoimmune and other diseases.

p38 activation and viral infection.

Viruses completely rely on the energy and metabolic systems of host cells for life activities. Viral infections usually lead to cytopathic effects and host diseases. To date, there are still no specific clinical vaccines or drugs against most viral infections. Therefore, understanding the molecular and cellular mechanisms of viral infections is of great significance to prevent and treat viral diseases. A variety of viral infections are related to the p38 MAPK signalling pathway, and p38 is an important host factor in virus-infected cells. Here, we introduce the different signalling pathways of p38 activation and then summarise how different viruses induce p38 phosphorylation. Finally, we provide a general summary of the effect of p38 activation on virus replication. Our review provides integrated data on p38 activation and viral infections and describes the potential application of targeting p38 as an antiviral strategy.

The Kv1.3 ion channel acts as a host factor restricting viral entry.

Virus entry into cells is the initial stage of infection and involves multiple steps, and interfering viral entry represents potential antiviral approaches. Ion channels are pore-forming membrane proteins controlling cellular ion homeostasis and regulating many physiological processes, but their roles during viral infection have rarely been explored. Here, the functional Kv1.3 ion channel was found to be expressed in human hepatic cells and tissues. The Kv1.3 was then revealed to restrict HCV entry via inhibiting endosome acidification-mediated viral membrane fusion. The Kv1.3 was also demonstrated to inhibit DENV and ZIKV with an endosome acidification-dependent entry, but have no effect on SeV with a neutral pH penetration. A Kv1.3 antagonist PAP-1 treatment accelerated animal death in ZIKV-infected Ifnar1-/- mice. Moreover, Kv1.3-deletion was found to promote weight loss and reduce survival rate in ZIKV-infected Kv1.3-/- mice. Altogether, the Kv1.3 ion channel behaves as a host factor restricting viral entry. These findings broaden understanding about ion channel biology.

The hypothalamus may mediate migraine and ictal photophobia: evidence from Granger causality analysis.

BACKGROUND: The hypothalamus plays a central role in the pathophysiology of migraine and is considered to be the "migraine generator." It participates in initiating a migraine attack through its connectivity to regions of the brain involved in processing and modulating pain. However, the underlying mechanisms of hypothalamic effective functional connectivity that bring about migraines remain unclear. This study investigated the hypothalamus-based directional effective connectivity in migraine without aura patients and assessed associations among the clinical characteristics. METHODS: Seven patients with migraine without aura during the attack (MWoA-DA) (four with photophobia (MWoA-DAWP) and three without photophobia (MWoA-DAWoP)), twenty-seven patients with migraine without aura during the interictal period (MWoA-DI), and twenty-nine healthy controls (HC) were included in this study. Granger causality analysis (GCA) was used to investigate the directional effective connectivity between the hypothalamus and other brain regions. RESULTS: MWoA-DA patients exhibited decreased outflow from the bilateral hypothalamus to the visual cortex compared with the MWoA-DI patients and HCs. The MWoA-DAWP group primarily contributed to this result. The MWoA-DA patients showed decreased outflow from the bilateral hypothalamus to the right inferior parietal gyrus compared with the HCs. The visual analogue scale (VAS) was negatively correlated with abnormal effective functional connectivity from the right hypothalamus to the right inferior parietal gyrus in the MWoA-DA group. CONCLUSIONS: These data provide evidence that the hypothalamus might serve as a central component of a multisystem network implicated in migraine and ictal photophobia, which includes hypothalamus and the visual and trigeminovascular systems.

Tick peptides evoke itch by activating MrgprC11/MRGPRX1 to sensitize TRPV1 in pruriceptors.

BACKGROUND: Tick bites severely threaten human health because they allow the transmission of many deadly pathogens, including viruses, bacteria, protozoa, and helminths. Pruritus is a leading symptom of tick bites, but its molecular and neural bases remain elusive. OBJECTIVES: This study sought to discover potent drugs and targets for the specific prevention and treatment of tick bite-induced pruritus and arthropod-related itch. METHODS: We used live-cell calcium imaging, patch-clamp recordings, and genetic ablation and evaluated mouse behavior to investigate the molecular and neural bases of tick bite-induced pruritus. RESULTS: We found that 2 tick salivary peptides, IP defensin 1 (IPDef1) and IR defensin 2 (IRDef2), induced itch in mice. IPDef1 was further revealed to have a stronger pruritogenic potential than IRDef2 and to induce pruritus in a histamine-independent manner. IPDef1 evoked itch by activating mouse MrgprC11 and human MRGPRX1 on dorsal root ganglion neurons. IPDef1-activated MrgprC11/X1 signaling sensitized downstream ion channel TRPV1 on dorsal root ganglion neurons. Moreover, IPDef1 also activated mouse MrgprB2 and its ortholog human MRGPRX2 selectively expressed on mast cells, inducing the release of inflammatory cytokines and driving acute inflammation in mice, although mast cell activation did not contribute to oxidated IPDef1-induced itch. CONCLUSIONS: Our study identifies tick salivary peptides as a new class of pruritogens that initiate itch through MrgprC11/X1-TRPV1 signaling in pruritoceptors. Our work will provide potential drug targets for the prevention and treatment of pruritus induced by the bites or stings of tick and maybe other arthropods.

The Pathophysiology of Long COVID throughout the Renin-Angiotensin System.

COVID-19 has expanded across the world since its discovery in Wuhan (China) and has had a significant impact on people's lives and health. Long COVID is a term coined by the World Health Organization (WHO) to describe a variety of persistent symptoms after acute SARS-CoV-2 infection. Long COVID has been demonstrated to affect various SARS-CoV-2-infected persons, independently of the acute disease severity. The symptoms of long COVID, like acute COVID-19, consist in the set of damage to various organs and systems such as the respiratory, cardiovascular, neurological, endocrine, urinary, and immune systems. Fatigue, dyspnea, cardiac abnormalities, cognitive and attention impairments, sleep disturbances, post-traumatic stress disorder, muscle pain, concentration problems, and headache were all reported as symptoms of long COVID. At the molecular level, the renin-angiotensin system (RAS) is heavily involved in the pathogenesis of this illness, much as it is in the acute phase of the viral infection. In this review, we summarize the impact of long COVID on several organs and tissues, with a special focus on the significance of the RAS in the disease pathogenesis. Long COVID risk factors and potential therapy approaches are also explored.

Angiotensin II Type I Receptor (AT1R): The Gate towards COVID-19-Associated Diseases.

The binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein to its cellular receptor, the angiotensin-converting enzyme 2 (ACE2), causes its downregulation, which subsequently leads to the dysregulation of the renin-angiotensin system (RAS) in favor of the ACE-angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis. AT1R has a major role in RAS by being involved in several physiological events including blood pressure control and electrolyte balance. Following SARS-CoV-2 infection, pathogenic episodes generated by the vasoconstriction, proinflammatory, profibrotic, and prooxidative consequences of the Ang II-AT1R axis activation are accompanied by a hyperinflammatory state (cytokine storm) and an acute respiratory distress syndrome (ARDS). AT1R, a member of the G protein-coupled receptor (GPCR) family, modulates Ang II deleterious effects through the activation of multiple downstream signaling pathways, among which are MAP kinases (ERK 1/2, JNK, p38MAPK), receptor tyrosine kinases (PDGF, EGFR, insulin receptor), and nonreceptor tyrosine kinases (Src, JAK/STAT, focal adhesion kinase (FAK)), and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. COVID-19 is well known for generating respiratory symptoms, but because ACE2 is expressed in various body tissues, several extrapulmonary pathologies are also manifested, including neurologic disorders, vasculature and myocardial complications, kidney injury, gastrointestinal symptoms, hepatic injury, hyperglycemia, and dermatologic complications. Therefore, the development of drugs based on RAS blockers, such as angiotensin II receptor blockers (ARBs), that inhibit the damaging axis of the RAS cascade may become one of the most promising approaches for the treatment of COVID-19 in the near future. We herein review the general features of AT1R, with a special focus on the receptor-mediated activation of the different downstream signaling pathways leading to specific cellular responses. In addition, we provide the latest insights into the roles of AT1R in COVID-19 outcomes in different systems of the human body, as well as the role of ARBs as tentative pharmacological agents to treat COVID-19.

Purlisin, a toxin-like defensin derived from clinical pathogenic fungus Purpureocillium lilacinum with both antimicrobial and potassium channel inhibitory activities.

Clinical fungal infections always cause a negative impact on human health. Moreover, during the interaction of pathogenic fungi with the environment and host, many biologically active substances are produced. Here, we report a new toxin-like defensin of purlisin derived from a clinical pathogenic isolate of Purpureocillium lilacinum. The analysis of its genomic and mRNA sequences revealed an open reading frame of 444 bp without introns. The deduced precursor peptide was composed of 147 amino acids, and the mature peptide were identified at protein level by LC-ESI-Q-TOF-MS/MS. After posttranslational processing, the precursor peptide of purlisin was split into two independent peptides. The two mature defensins, purlisin-NT and purlisin-CT, are consisting of 36 and 38 amino acid residues, which can form three and four intramolecular disulfide bonds, respectively. The results of circular dichroism and homology modeling revealed that they adopted a representative cysteine-stabilized α-helical and ß-sheet motif. The purlisin-NT showed a dose-dependent selective inhibition of immune-related hKv1.3 target channel with IC50 value of 0.2 ± 0.04 µM but no obvious antibacterial activity, while the purlisin-CT displayed antimicrobial activities against gram-positive bacteria as well as clinical isolates of MRSA and low affinities for potassium channels. Our findings suggest that purlisin-NT with immunosuppressive effects and purlisin-CT possessing antibacterial activities are adapted to the survival and pathogenicity of clinical P lilacinumis. Moreover, they can also be used as templates for the design of novel antibacterial peptide and immunosuppressive agents.

The Renin-Angiotensin System: A Key Role in SARS-CoV-2-Induced COVID-19.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), was first identified in Eastern Asia (Wuhan, China) in December 2019. The virus then spread to Europe and across all continents where it has led to higher mortality and morbidity, and was declared as a pandemic by the World Health Organization (WHO) in March 2020. Recently, different vaccines have been produced and seem to be more or less effective in protecting from COVID-19. The renin-angiotensin system (RAS), an essential enzymatic cascade involved in maintaining blood pressure and electrolyte balance, is involved in the pathogenicity of COVID-19, since the angiotensin-converting enzyme II (ACE2) acts as the cellular receptor for SARS-CoV-2 in many human tissues and organs. In fact, the viral entrance promotes a downregulation of ACE2 followed by RAS balance dysregulation and an overactivation of the angiotensin II (Ang II)-angiotensin II type I receptor (AT1R) axis, which is characterized by a strong vasoconstriction and the induction of the profibrotic, proapoptotic and proinflammatory signalizations in the lungs and other organs. This mechanism features a massive cytokine storm, hypercoagulation, an acute respiratory distress syndrome (ARDS) and subsequent multiple organ damage. While all individuals are vulnerable to SARS-CoV-2, the disease outcome and severity differ among people and countries and depend on a dual interaction between the virus and the affected host. Many studies have already pointed out the importance of host genetic polymorphisms (especially in the RAS) as well as other related factors such age, gender, lifestyle and habits and underlying pathologies or comorbidities (diabetes and cardiovascular diseases) that could render individuals at higher risk of infection and pathogenicity. In this review, we explore the correlation between all these risk factors as well as how and why they could account for severe post-COVID-19 complications.

Increased grey matter volume and associated resting-state functional connectivity in chronic spontaneous urticaria: A structural and functional MRI study.

BACKGROUND AND PURPOSE: Chronic itch is one of the most common irritating sensations, yet its mechanisms have not been fully elucidated. Although some studies have revealed relationships between itching and brain function, the structural changes in the brain induced by chronic itching, such as those accompanying chronic spontaneous urticaria (CSU), remain unclear. In this study, we aimed to explore the potential changes in brain structure and the associated functional circuitry in CSU patients to generate insights to aid chronic itch management. METHODS: Forty CSU patients and forty healthy controls (HCs) were recruited. Seven-day urticaria activity score (UAS7) values were collected to evaluate clinical symptoms. Voxel-based morphometry (VBM) and seed-based resting-state functional connectivity (rs-FC) analysis were used to assess structural changes in the brain and associated changes in functional circuitry. RESULTS: Compared with HCs, CSU patients had significantly increased grey matter (GM) volume in the right premotor cortex, left fusiform cortex, and cerebellum. UAS7 values were positively associated with GM volume in the left fusiform cortex. In CSU patients relative to HCs, the left fusiform cortex as extracted by VBM analysis demonstrated decreased functional connectivity with the right orbitofrontal cortex, medial prefrontal cortex (mPFC), premotor cortex, primary motor cortex (MI), and cerebellum and increased functional connectivity with the right posterior insular cortex, primary somatosensory cortex (SI), and secondary somatosensory cortex (SII). The left cerebellum as extracted from VBM analysis demonstrated decreased functional connectivity with the right supplementary motor area (SMA) and MI in CSU patients relative to HCs. CONCLUSIONS: Our findings indicate that patients suffering from chronic itching conditions, such as CSU, are likely to demonstrate altered GM volume in some brain regions. These changes may affect not only the sensorimotor area but also brain regions associated with cognitive function.

A scorpion venom peptide Ev37 restricts viral late entry by alkalizing acidic organelles.

Viral infections still threaten human health all over the world, and many people die from viral diseases every year. However, there are no effective vaccines or drugs for preventing or managing most viral diseases. Thus, the discovery and development of broad-spectrum antiviral agents remain urgent. Here, we expressed and purified a venom peptide, Ev37, from the scorpion Euscorpiops validus in a prokaryotic system. We found that rEv37 can inhibit dengue virus type 2 (DENV-2), hepatitis C virus (HCV), Zika virus (ZIKV), and herpes simplex virus type 1 (HSV-1) infections in a dose-dependent manner at noncytotoxic concentrations, but that it has no effect on Sendai virus (SeV) and adenovirus (AdV) infections in vitro Furthermore, rEv37 alkalized acidic organelles to prevent low pH-dependent fusion of the viral membrane-endosomal membrane, which mainly blocks the release of the viral genome from the endosome to the cytoplasm and then restricts viral late entry. Taken together, our results indicate that the scorpion venom peptide Ev37 is a broad-spectrum antiviral agent with a specific molecular mechanism against viruses undergoing low pH-dependent fusion activation during entry into host cells. We conclude that Ev37 is a potential candidate for development as an antiviral drug.

Rosehip Oil Promotes Excisional Wound Healing by Accelerating the Phenotypic Transition of Macrophages.

Poor wound healing is a major and global threat to public health. Efforts have been made to better understand the underlying mechanisms and develop effective remedies, though the advancements that have been made are still limited. As there are no effective and generally applicable therapies available for skin injuries and fibrosis, it is urgent to develop new drugs and therapies that facilitate wound healing and effectively improve scars. In this study, GC-MS analysis was performed to identify the chemical composition of rosehip oil. The excisional wound healing model and the carrageenan-induced paw edema method were respectively applied to evaluate the wound healing activity and anti-inflammatory activity of rosehip oil. Hematoxylin and eosin staining was used to assess the pathological changes of sections, and Sirius-red staining was performed to analyze the ratio of collagen I/III in wound tissues. Immunohistological staining for CD68, CCR7 (CD197), CD163, TGF-ß1, and α-SMA was applied to determine the macrophage phenotypes transition (M1-to-M2) and demonstrate the scar-improving efficacy of rosehip oil on wound healing. Results showed that rosehip oil significantly promoted wound healing and effectively improved scars. This efficacy might be exerted by accelerating the macrophage phenotypes transition and inhibiting the process of epithelial-mesenchymal transition.

Diverse Structural Features of Potassium Channels Characterized by Scorpion Toxins as Molecular Probes.

Scorpion toxins are well-known as the largest potassium channel peptide blocker family. They have been successfully proven to be valuable molecular probes for structural research on diverse potassium channels. The potassium channel pore region, including the turret and filter regions, is the binding interface for scorpion toxins, and structural features from different potassium channels have been identified using different scorpion toxins. According to the spatial orientation of channel turrets with differential sequence lengths and identities, conformational changes and molecular surface properties, the potassium channel turrets can be divided into the following three states: open state with less hindering effects on toxin binding, half-open state or half-closed state with certain effects on toxin binding, and closed state with remarkable effects on toxin binding. In this review, we summarized the diverse structural features of potassium channels explored using scorpion toxin tools and discuss future work in the field of scorpion toxin-potassium channel interactions.