Journal of General Physiology最新文献

{"title":"Extrinsic inputs underscore heterogeneities of ELL pyramidal cell neural activity in awake, behaving weakly electric fish.","authors":"Amin Akhshi, Myriah Haggard, Mariana M Marquez, Saeed Farjami, Maurice J Chacron, Anmar Khadra","doi":"10.1085/jgp.202513841","DOIUrl":"https://doi.org/10.1085/jgp.202513841","url":null,"abstract":"<p><p>Heterogeneity in spiking activity is ubiquitous among neurons even within a given cell type. To date, the relative contributions of extrinsic mechanisms (e.g., synaptic bombardment), intrinsic mechanisms (e.g., conductances), and cell morphology toward determining spiking activity remain poorly understood. Here, we addressed this important question using a combination of extracellular in vivo recordings of electrosensory pyramidal cells within weakly electric fish with computational modeling. Specifically, by varying parameters of a conductance-based computational model, we successfully reproduced the highly heterogeneous spiking activities seen experimentally. Model parameters that varied the most were then used to gauge the relative contributions of extrinsic vs. intrinsic mechanisms. Overall, extrinsic synaptic input was predicted to be the main factor accounting for spiking heterogeneity. We tested this prediction experimentally by performing two different manipulations: (1) pharmacologically inactivating feedback from higher brain areas and (2) applying the neuromodulator serotonin. Our model showed that feedback inactivation should reduce spiking heterogeneity, whereas serotonin application should increase it, two predictions that were corroborated experimentally. Importantly, for serotonin application, increased heterogeneity occurred despite a strong reduction in intrinsic membrane conductance, further demonstrating that extrinsic synaptic input is the primary determinant of spiking heterogeneity in vivo. Taken together, our results demonstrate that devising a computational model to capture spiking heterogeneities in vivo and assessing which parameters are responsible can successfully determine the relative contributions of extrinsic inputs, intrinsic properties, and neural morphology.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolution of our understanding of the sodium channel fast inactivation: From Hodgkin and Huxley to the structural era.","authors":"Yichen Liu, Cesar A Amaya-Rodriguez, Victoria Collio, Gabriel Ibañez, Ramón Latorre, Francisco Bezanilla","doi":"10.1085/jgp.202613980","DOIUrl":"https://doi.org/10.1085/jgp.202613980","url":null,"abstract":"<p><p>Voltage-gated sodium (Nav) channels enable the rapid influx of sodium ions that are essential to generating the rising phase of the action potential. As originally described by Hodgkin and Huxley, once the Nav channel is activated, it switches to an inactivated state within milliseconds, a process they called inactivation. Internal perfusion of the giant axon of the squid with proteolytic enzymes eliminated inactivation, implying that the inactivation gate is an internal protein structure of the Nav channel. This result, together with the charge immobilization of the gating currents, led to the ball and chain model of inactivation. Deletion of the linker between domains III and IV of the four homologous domains of the Nav channel was found to remove fast inactivation. These observations evolved the ball and chain model to the hinged-lid model of fast inactivation, which dominated the field for nearly 30 years. Surprisingly, the structures of the Nav channel, determined by cryo-EM, showed that the IFM was not at the site predicted by the hinged-lid model. Upending the Na channel field, biophysical and mutagenesis studies revealed that the binding of the IFM motif allosterically closes an inactivation gate at the internal entrance of the Nav conduction system. In this Review, we compile the historical and structural evolution of the fast inactivation process, from the first functional descriptions to current models based on structural data.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147846260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deep learning as a generator of sodium channel state hypotheses.","authors":"Lisa Schmidt, Wojciech Kopec","doi":"10.1085/jgp.202513938","DOIUrl":"https://doi.org/10.1085/jgp.202513938","url":null,"abstract":"<p><p>Lopez-Mateos et al. show that AlphaFold 2 can generate structural ensembles of NaV channels and that β-subunits and calmodulin reshape these ensembles, while emphasizing that these are testable structural hypotheses, not actual thermodynamic populations.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147437675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sequential membrane remodeling by cholesterol distinctly modulates HCN channels in naïve and neuropathic DRG neurons.","authors":"Lucas J Handlin, Clémence Gieré, Nicolas L A Dumaire, Lyuba Salih, Aubin Moutal, Gucan Dai","doi":"10.1085/jgp.202513925","DOIUrl":"10.1085/jgp.202513925","url":null,"abstract":"<p><p>Cholesterol, abundantly present in distinct plasma membrane pools, is a critical modulator of ion channel function, including hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that regulate the excitability of dorsal root ganglion (DRG) nociceptor neurons. Depletion of membrane cholesterol potentiated HCN channel opening and accelerated activation kinetics, whereas cholesterol supplementation reduced channel opening and slowed activation kinetics. However, the relative contributions of cholesterol that organizes ordered membrane domains (OMDs) versus freely accessible cholesterol pools to HCN channel modulation remain unknown. Using fluorescence lifetime imaging microscopy, FRET and fluorescence anisotropy techniques, we examined how supplementing cholesterol alters plasma membrane properties and HCN gating in nociceptor DRG neurons. We uncovered a process of sequential, stepwise membrane remodeling: an initial phase with OMD expansion and a rapid rise in free cholesterol, followed by continued accumulation of free cholesterol without further OMD expansion. Notably, the slope factor of the HCN G-V relationship is sensitive to OMD expansion but remains unaffected by changes in free cholesterol. Other gating parameters, including open probability and activation kinetics, were affected by elevating free cholesterol. In a rat model of nerve injury, where DRG neurons exhibit reduced free cholesterol levels and smaller OMDs, HCN channel modulation by cholesterol involves contributions from both OMD expansion and free cholesterol accumulation. In contrast, in naïve DRG neurons-characterized by high cholesterol and large OMDs-modulation occurs mostly via increased free cholesterol. These findings provide mechanistic insights into cholesterol-dependent modulation of ion channels and its role in neuropathic pain.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12981344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147446028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diminished gap junction coupling under diabetogenic conditions does not drive loss of functional β-cell subpopulations.","authors":"Claire H Levitt, Dominic Isaacs, Maria S Hansen, Vira Kravets, Jennifer K Briggs, Richard K P Benninger","doi":"10.1085/jgp.202513867","DOIUrl":"10.1085/jgp.202513867","url":null,"abstract":"<p><p>Within the islets of Langerhans, gap junction coupling is important for synchronizing oscillatory free-calcium activity ([Ca2+]) and regulating pulsatile insulin release. In islets from multiple models of diabetes, gap junction coupling is disrupted, and [Ca2+] synchronization and pulsatile insulin is lost. Functional subpopulations have been identified within the islet that are linked to driving synchronized [Ca2+] and insulin release. These subpopulations can be disrupted under conditions associated with diabetes, such as glucolipotoxicity and inflammatory environments, and their loss may drive islet dysfunction. Here we investigated how loss of gap junction coupling influences functional subpopulations under diabetogenic environments. We treated islets with a cocktail of pro-inflammatory cytokines and protected gap junction coupling via co-treatment with a Cx36 peptide S293 that was previously shown to specifically prevent a decline in gap junction permeability and synchronized [Ca2+] dynamics. We performed calcium imaging and ChR2 stimulation and analyzed islet [Ca2+] dynamics and the presence of functional subpopulations, including hubs and first-responders. 1- or 24-h cytokine treatment disrupted gap junction coupling, which was fully prevented by S293 peptide co-treatment. Treatment with pro-inflammatory cytokines decreased the recruitment of [Ca2+] upon ChR2 stimulation, increased the time between first and last responding cells upon glucose stimulation, and reduced the number and consistency of hub cells. When preserving gap junction coupling by S293 during cytokine treatment, the presence and consistency of these subpopulations were only marginally improved. We therefore concluded that while gap junction coupling is important for functional subpopulations to exert their influence on islet function, the restoration of gap junctions alone is not sufficient to recover functional subpopulations under diabetogenic conditions. Thus, preventing a disruption to intrinsic β-cell properties that define functional subpopulations is likely important for preserving these subpopulations during diabetes.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147582970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinctive mechanical response characteristics of the guinea pig apical cochlear organ of Corti and basilar membrane.","authors":"George W S Burwood, Tianying Ren, Edward V Porsov, Alfred L Nuttall, Anders Fridberger","doi":"10.1085/jgp.202413611","DOIUrl":"https://doi.org/10.1085/jgp.202413611","url":null,"abstract":"<p><p>Upon acoustic stimulation of the mammalian cochlea, a travelling wave will move in a base-to-apex direction, peaking close to the resonant place of the basilar membrane. A gradient of different resonances along the basilar membrane gives rise to frequency-place coding, or tonotopicity, throughout the majority of the cochlea. Per our previous findings, the organ of Corti in the guinea pig cochlear apex does not display tonotopicity. The behavior of the basilar membrane has not been explored throughout the cochlear apex, and so hypothetically tonotopicity is conserved at the level of this structure. Outer hair cells, which influence organ of Corti and basilar membrane mechanics, provide amplification throughout the cochlea. The mechanism for this process in the region close to the helicotrema, which is important for speech and music perception, is not fully described. Here, we describe the acoustically evoked vibrations measured using optical coherence tomography (OCT) at three locations within the guinea pig cochlear apex. We note a decline in the ratio of organ of Corti and basilar membrane gain with proximity to the helicotrema and show that distinct nonlinear behaviors are associated with each location. Phase differences between the cellular portion of the organ of Corti and basilar membrane were present and remained after furosemide treatment. We report that the frequency tuning of the apical basilar membrane is inconsistent with standard models. The analysis of nonlinearity indicates that the mechanisms governing sensory transduction, while still not elucidated, change rapidly within the apical turn-findings that are important for understanding how communication-relevant sounds are encoded by the cochlea.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13101915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Putative RNA editing of a nicotinic receptor increases acetylcholine sensitivity.","authors":"Cecilia M Borghese, Ying Lu, Edward J Bertaccini, Harold H Zakon","doi":"10.1085/jgp.202413677","DOIUrl":"https://doi.org/10.1085/jgp.202413677","url":null,"abstract":"<p><p>Regulation of the agonist sensitivity of neurotransmitter receptors is critical for proper functioning of neuronal circuits and is, therefore, conserved across evolutionary time. Mutations that alter agonist sensitivity are often pathological in humans. A brain-expressing nicotinic acetylcholine receptor (nAChR) from the frog Xenopus tropicalis shows ∼20× greater sensitivity to ACh as orthologs from human, chickens, and other frogs prompt us to examine the molecular basis for this extreme sensitivity. We identified a single amino acid substitution in the third transmembrane domain (M3) of the X. tropicalis α4 nAChR subunit, F294 (S in other vertebrate orthologs), that confers the high sensitivity. Surprisingly, we noted variation at this site in sequences deposited in NCBI, suggesting either allelic variation or RNA editing. By sequencing genomic DNA and mRNA (cDNA) from the same individuals from two different colonies of X. tropicalis, we determined that a possible source of this variation is RNA editing. The unedited receptor from X. tropicalis (S294) has a similar ACh sensitivity as those from other vertebrates. Further work must be done to examine possible adaptations of edited receptors and if the frog's brain compensates for an increase in sensitivity since increases in agonist sensitivity lead to pathology in humans.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147272888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Missense mutation causes multiple defects in Nav1.4 channel gating and leads to an SCN4A-associated overlap phenotype.","authors":"Tatiana B Tikhonova, Artem A Sharkov, Aysylu F Murtazina, Nadezda V Mashkovtseva, Boris S Zhorov, Alexander A Vassilevski","doi":"10.1085/jgp.202413706","DOIUrl":"https://doi.org/10.1085/jgp.202413706","url":null,"abstract":"<p><p>Mutations in SCN4A gene encoding the skeletal muscle-type voltage-gated sodium channel Nav1.4 are known to cause neuromuscular disorders. Here, we report a previously undescribed variant affecting the DIII-IV cytoplasmic linker, which is a critically important region participating in channel inactivation. The variant p.L1326P was found in heterozygous state in two members of the same family presenting mild symptoms of periodic paralysis and in vivo electrophysiological features of sodium channel myotonia. Functional characterization was performed using Xenopus oocytes co-expressing human Nav1.4 and β1 subunits, and the two-electrode voltage clamp technique. We recorded gating alterations in Nav1.4-L1326P compared with wild-type channels. (1) The voltage dependence of activation shifted to the depolarizing direction, whereas (2) the voltage dependence of steady-state inactivation moved in the hyperpolarizing direction. (3) Fast channel inactivation was markedly decelerated in Nav1.4-L1326P. In addition, (4) we observed a dramatic increase in persistent current. The gain-of-function effects are consistent with the consensus view on the pathogenesis of myotonia and periodic paralysis. AlphaFold 3 models suggest stronger contacts between the cytoplasmic domain and the DIII-IV linker in the mutant channels offering a possible structural interpretation of the functional changes.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-function analysis of the lithium-ion selectivity of the voltage-gated sodium channel.","authors":"Yuki K Maeda, Kentaro Kojima, Tomoe Y Nakamura, Toru Nakatsu, Katsumasa Irie","doi":"10.1085/jgp.202513855","DOIUrl":"10.1085/jgp.202513855","url":null,"abstract":"<p><p>Voltage-gated sodium channels (Navs) selectively conduct Na+ to generate action potentials. Na+ permeates Navs with significantly higher efficiency than many other cations, but Li+ can also permeate Navs to an extent comparable with Na+. Li+ in the blood is known to enter cells via Navs and to have a beneficial effect on various neuropathies. However, the molecular basis of the high Li+ selectivity of Navs was unclear. In this study, using a prokaryotic Nav, we successfully created the first Nav mutant to be more selective for Li+ than for Na+. Electrophysiological and crystallographic analyses suggested the critical determinants of high Li+ selectivity: the strong electrostatic interaction between the ion pathway and hydrated ions, and the smaller number of hydration water exchanges within the ion pathway. Additionally, the extensive interactions around the ion pathway were shown to support monovalent cation selectivity. New drug directions based on the molecular basis for Li+ permeation may target various neurological disorders and could clarify the broader biological effects of lithium.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12919392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146229795","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol pools cooperate to modulate HCN channels.","authors":"Ben Short","doi":"10.1085/jgp.202614013","DOIUrl":"https://doi.org/10.1085/jgp.202614013","url":null,"abstract":"<p><p>JGP study (Handlin et al. https://doi.org/10.1085/jgp.202513925) provides new mechanistic insights into the cholesterol-dependent modulation of pain sensation by DRG neurons.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147789727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}