Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain

Chi, Gamma; Liang, Qiansheng; Sridhar, Akshay; Cowgill, John; Sader, Kasim; Radjainia, Mazdak; Qian, Pu; Castro‐Hartmann, Pablo; Venkaya, S.; Singh, Nanki Kaur; McKinley, G.; Fernández-Cid, Alejandra; Mukhopadhyay, S.M.M.; Burgess-Brown, N.; Delemotte, Lucie; Covarrubias, Manuel; Dürr, Katharina L.

doi:10.1038/s41467-022-29594-w

Cited by 22 publications

(30 citation statements)

References 76 publications

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“…For example, structures of rat Kv1.2, human Kv1.3, and human Kv3.1 all possess large vestibules, and a selectivity filter that would be sufficient to accommodate 4-AP ( SI Appendix , Fig. S8 ) ( 23 – 25 ). Moreover, similar to TMEM175, a K + ion occupies the putative 4-AP binding site in the structure of rat Kv1.2 ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175

Stix

Zhou

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Transmembrane protein 175 (TMEM175) is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson’s disease. Here, we present a cryoelectron microscopy structure and molecular simulations of TMEM175 bound to 4-aminopyridine (4-AP), the only known small-molecule inhibitor of TMEM175 and a broad K + channel inhibitor, as well as a drug approved by the Food and Drug Administration against multiple sclerosis. The structure shows that 4-AP, whose mode of action had not been previously visualized, binds near the center of the ion conduction pathway, in the open state of the channel. Molecular dynamics simulations reveal that this binding site is near the middle of the transmembrane potential gradient, providing a rationale for the voltage-dependent dissociation of 4-AP from TMEM175. Interestingly, bound 4-AP rapidly switches between three predominant binding poses, stabilized by alternate interaction patterns dictated by the twofold symmetry of the channel. Despite this highly dynamic binding mode, bound 4-AP prevents not only ion permeation but also water flow. Together, these studies provide a framework for the rational design of novel small-molecule inhibitors of TMEM175 that might reveal the role of this channel in human lysosomal physiology both in health and disease.

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Section: Discussionmentioning

confidence: 99%

Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175

Stix

Zhou

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…KCNC1 is highly and exclusively expressed in the cerebellum based on GTEx and encodes member 1, subfamily C of integral membrane proteins that mediate the voltage-dependent potassium ion permeability of excitable membranes. This protein is the key to K+ voltage-dependent channel Kv3 48,49 . Kv3 channels regulate neurotransmitter release 50 , particularly affecting the high-frequency firing of neuron 51 including circadian rhythms in the suprachiasmatic nucleus of the hypothalamus 52 .…”

Section: Discussionmentioning

confidence: 99%

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression

Thapaliya

Ray

Farahdel

et al. 2023

Preprint

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Anxiety and depression in children and adolescents warrant special attention as a public health issue given their devastating and long-term effects on development and mental health. Multiple factors, ranging from genetic vulnerabilities to environmental stressors, influence the risk for the disorders. This study aimed to understand how environmental factors and genomics affect children and adolescents anxiety and depression across three cohorts: Adolescent Brain and Cognitive Development Study (US, age of 9-10), Consortium on Vulnerability to Externalizing Disorders and Addictions (INDIA, age of 6-17) and IMAGEN (EUROPE, age of 14). We performed data harmonization and identified the environmental impact on anxiety/depression using a linear mixed-effect model, recursive feature elimination regression, and the LASSO regression model. Subsequently, genome-wide association analyses with consideration of significant environmental factors were performed for all three cohorts by mega-analysis and meta analysis, followed by functional annotations. The results showed that multiple environmental factors contributed to the risk of anxiety and depression during development, where early life stress and school risk had the most significant and consistent impact across all three cohorts. Both meta and mega-analysis identified a novel SNP rs79878474 in chr11p15 to be the most promising SNP associated with anxiety and depression. Gene set analysis on the common genes mapped from top promising SNPs of both meta and mega analyses found significant enrichment in regions of chr11p15 and chr3q26, in the function of potassium channels and insulin secretion, in particular Kv3, Kir-6.2, SUR potassium channels encoded by the KCNC1, KCNJ11, and ABCCC8 genes respectively, in chr11p15. Tissue enrichment analysis showed significant enrichment in the small intestine and a trend of enrichment in the cerebellum. Our findings provide evidence of consistent environmental impact from early life stress and school risks on anxiety and depression during development and also highlight the genetic association between mutations in potassium channels along with the potential role of the cerebellum region, which are worthy of further investigation.

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“…Recent publication of the cryo‐EM structure of human Kv3.1 provides unprecedented insight into the mechanism of gating of Kv3 channels. 14 The Met430 residue has been shown to contribute to ion conduction and regulate Kv3.1 pore stability as mutation of this residue to a lysine induces channel flicker, 15 while the cryo‐EM structure reveals that the Met430 residue in S6 forms a intersubunit sulfo‐aromatic interaction with the F345 residue in S5 of adjacent subunits. Why the variant KCNC1 ‐p.Ala421Val located slightly more proximal – and which also converts between two small amino acids with hydrophobic side chains – instead produces a profound LoF (and the more severe DEE) remains unclear.…”

Section: Discussionmentioning

confidence: 99%

A KCNC1‐related neurological disorder due to gain of Kv3.1 function

Clatot

Ginn

Costain

et al. 2022

Ann Clin Transl Neurol

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Objective To further clarify genotype:phenotype correlations associated with variants in KCNC1 encoding the voltage‐gated potassium (K+) channel subunit Kv3.1 and which are an emerging cause of a spectrum of neurological disease including intellectual disability, isolated myoclonus, progressive myoclonus epilepsy, and developmental and epileptic encephalopathy. Methods We describe the clinical and genetic characteristics of a series of three patients with de novo heterozygous missense variants in KCNC1 associated with nonspecific developmental delay/intellectual disability and central hypotonia without epilepsy or ataxia. All three variants lead to amino acids alterations with mild predicted differences in physicochemical properties yet are localized to the S6 pore region of the Kv3.1 protein between the selectivity filter and PXP motif important for K+ channel gating. We performed whole‐cell voltage clamp electrophysiological recording of wild‐type versus variants in a heterologous mammalian expression system. Results We demonstrate a prominent leftward (hyperpolarized) shift in the voltage dependence of activation and slowed deactivation of all variants in the clinically defined series. Interpretation Electrophysiological recordings are consistent with a gain of K+ channel function that is predicted to exert a loss of function on the excitability of Kv3‐expressing high frequency‐ firing neurons based on the unique electrophysiological properties of Kv3 channels. These results define a clinical‐genetic syndrome within the spectrum of KCNC1 ‐related neurological disorders.

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Cryo-EM structure of the human Kv3.1 channel reveals gating control by the cytoplasmic T1 domain

Cited by 22 publications

References 76 publications

Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175

Mechanism of 4-aminopyridine inhibition of the lysosomal channel TMEM175

Cross-continental environmental and genome-wide association study on children and adolescent anxiety and depression

A KCNC1‐related neurological disorder due to gain of Kv3.1 function

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