Journal of General Physiology最新文献

{"title":"Communication breakdown: Impaired pericyte KATP channels in a model of Alzheimer's disease.","authors":"William F Jackson","doi":"10.1085/jgp.202614120","DOIUrl":"https://doi.org/10.1085/jgp.202614120","url":null,"abstract":"<p><p>The brain requires a continuous supply of blood in proportion to its metabolic activity, a process that is disrupted in Alzheimer's disease. However, the mechanisms responsible for altered brain blood flow regulation in Alzheimer's disease remain poorly defined. In an earlier issue of JGP, Hariharan et al. (https://doi.org/10.1085/jgp.202614014) significantly add to our understanding of this pathology by showing that ATP-Sensitive K+ (KATP) channels in thin strand pericytes on cerebral capillaries are compromised at 6-8 weeks in the 5X-FAD mouse model of Alzheimer's disease. They also confirmed that cerebral capillary endothelial inward rectifier K+ (KIR) channels are crippled and importantly show that this defect occurs at 2-4 months, before significant cognitive defects have been reported. Combined, these channelopathies severely attenuate electrical communication along cerebral capillaries, dampening blood flow regulation. These novel findings present new therapeutic targets to slow or possibly prevent the reduced cerebral blood flow in Alzheimer's disease, perhaps delaying or preventing cognitive decline. Like all scientific advances, they also open the door for new areas of research.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"159 1","pages":""},"PeriodicalIF":3.2,"publicationDate":"2027-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149290038","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":"Tunable AMPA receptor function via recurrent evolution of heterotetramers.","authors":"Yuhong Wang, Alexander Edwards, Jelena Baranovic, Timothy Lynagh","doi":"10.1085/jgp.202614039","DOIUrl":"10.1085/jgp.202614039","url":null,"abstract":"<p><p>Most ionotropic neurotransmitter receptors are hetero-oligomers of three to five homologous subunits assembled into membrane-spanning ion channels. Mammalian AMPA-type glutamate receptors (AMPARs), which emerged in animals with centralized nervous systems and now mediate most of the excitatory synaptic signaling in our brain, readily assemble as homotetramers, yet often occur as heterotetramers of two to three different AMPAR subunits. Here, we looked for unifying functional properties of the AMPAR family using molecular phylogenetics, together with electrophysiological and pharmacological characterization of heterologously expressed AMPARs from the three major lineages within bilaterian animals. Our results suggest that the hallmark of AMPAR evolution is selective activation by glutamate, fast kinetics, and the duplication of AMPAR genes independently in new animal lineages, such that most major bilaterian groups have relatively unique complements of AMPAR genes. Moreover, in diverse bilaterians, these novel AMPAR subunits have (1) come to rely on each other for functional expression, resulting in obligate heterotetrameric AMPARs, and (2) sub-functionalized, with various subunits contributing differently to channel activation or ion permeation. Remarkably, this evolution appears to have independently converged on a complement of calcium-sensitive and calcium-insensitive AMPARs in mammals and worms via biophysically similar but genetically different mechanisms.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834773","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":"Diastolic contributors in cardiomyocytes of a cardiometabolic HFpEF-like mouse model.","authors":"Arooj Shahid, Timothy S McMillen, Samuel Daugherty, Anna E Burns, Marloes van den Berg, Michael Regnier, Henk Granzier, Mei Methawasin","doi":"10.1085/jgp.202614028","DOIUrl":"10.1085/jgp.202614028","url":null,"abstract":"<p><p>Three main contributors to cardiomyocyte diastolic stiffness are (1) passive sarcomere stiffness, (2) microtubules, and (3) diastolic crossbridges (XBs), the XBs that are present in the diastolic phase. However, the relative contributions of these key determinants in heart failure with preserved ejection fraction (HFpEF) conditions are unclear. We quantify the relative contributions of passive sarcomere stress, the microtubule network, and diastolic XB activity to overall diastolic stress in intact cardiomyocytes isolated from two-hit mice, a cardiometabolic HFpEF-like model, in both sexes. The stretch-release protocol was used to obtain the diastolic stress-sarcomere length relation. XB inhibitor and colchicine treatment were used to determine the contributions of diastolic XBs and microtubules, respectively. Passive sarcomere stress was measured in cells treated with both colchicine and the XB inhibitor. Male HFpEF-like cardiomyocytes exhibit increases in both passive sarcomere stress (by 70%) and diastolic XBs (by 52%), whereas female HFpEF-like cardiomyocytes show an increase in passive sarcomere stress alone (by 55%). The microtubule network contributes to diastolic stress by augmenting the extent of diastolic XBs in males. The elevated diastolic XBs in male HFpEF-like mice are accompanied by altered Ca2+ transient, suggesting that remodeled Ca2+ handling accounts, in part, for the enhanced diastolic XB activity in males. These findings imply that, in males, both increased passive sarcomere stiffness and diastolic XB activity represent potential therapeutic targets for reducing cardiomyocyte diastolic stiffness, whereas in females, diastolic stiffness is predominantly driven by elevated passive sarcomere stiffness.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13505484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148814920","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":"The proximal N terminus of IRAG is required for potentiation of HCN4 channels.","authors":"Lucas M Blecker, Emily M Teichman, Colin H Peters, Daniel J Enders, Rebecca Roth, William G Nichols, Avery A Langley, Catherine Proenza, John R Bankston","doi":"10.1085/jgp.202614032","DOIUrl":"10.1085/jgp.202614032","url":null,"abstract":"<p><p>The inositol triphosphate-associated, ER transmembrane proteins inositol triphosphate receptor-associated guanylate kinase substrate (IRAG) and lymphoid restricted membrane protein (LRMP) are isoform-specific regulators of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4, while IRAG mimics the effect of cAMP on the channel. We previously showed that regulation by LRMP requires both the N terminus of HCN4 as well as a unique set of residues in the cAMP transduction center of HCN4, which is comprised of the N-terminal HCN domain (HCND), the C-linker, and the S4-S5 linker. However, it remains unknown if the homologous IRAG requires similar structural features to mimic cAMP-dependent potentiation, or if the site and mechanism of action are different between the two regulators. Using patch-clamp electrophysiology, we determined that the initial 43 amino acids of IRAG are necessary and sufficient to confer regulation of HCN4. Similar to LRMP, IRAG also requires a portion of the N terminus of HCN4 to confer its regulatory effects. Also like LRMP, two point mutations in the C-linker region, near where the C-linker of one subunit contacts its neighboring subunit, were able to eliminate the effect of IRAG. Taken together, these findings suggest a model whereby IRAG and LRMP make complex interactions with a number of intracellular domains of HCN4. For both proteins, regulation of HCN4 requires a portion of the N terminus and at least some portions of the structural domains required to convert the binding of cAMP to the cyclic nucleotide-binding domain (CNBD) to a change in channel gating.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148921925","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":"Correction: Evolution, hibernation, and inactivation of voltage-gated Na channels.","authors":"John S Willis","doi":"10.1085/jgp.20251392308102026c","DOIUrl":"10.1085/jgp.20251392308102026c","url":null,"abstract":"","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148867958","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":"Chamber-specific regulation of myofilament Ca2+ sensitivity by nNOSβ via troponin I phosphorylation: Predominance in the right ventricle.","authors":"Jae Won Kwon, Hyerim Park, Ryeon Heo, Jihyun Jang, Jintae Kim, Seung Beom Oh, Yin Hua Zhang, Sung Joon Kim, Young Keul Jeon","doi":"10.1085/jgp.202613982","DOIUrl":"https://doi.org/10.1085/jgp.202613982","url":null,"abstract":"<p><p>Neuronal nitric oxide (NO) synthase (nNOS) is an important regulator of excitation-contraction coupling in cardiomyocytes, yet its chamber-specific role in right ventricular cardiomyocytes (RVCMs) remains incompletely understood. In this study, we compared the effects of nNOS inhibition on contractile function, Ca2+ signaling, and myofilament-associated regulation in RVCMs and left ventricular cardiomyocytes (LVCMs). Pharmacological inhibition of nNOS with S-methyl-L-thiocitrulline (SMTC) enhanced sarcomere shortening and impaired relaxation in both cell types, with markedly greater effects observed in RVCMs. In contrast, SMTC-induced changes in Ca2+ transients and L-type Ca2+ current were more pronounced in LVCMs than in RVCMs, indicating a dissociation between Ca2+ signaling and mechanical responses in the SMTC-treated RVCMs. Analysis of dynamic Ca2+-sarcomere length coupling indicated that nNOS inhibition in RVCMs preferentially altered the relationship between intracellular Ca2+ signaling and sarcomere response, particularly during relaxation, rather than simply reflecting changes in Ca2+ magnitude. Consistent with this interpretation, inhibition of nNOS reduced cardiac troponin I (cTnI) Ser23/24 phosphorylation and was associated with altered endogenous Ca2+ buffering properties in RVCMs. Moreover, myofilament-enriched fractions from RVCMs exhibited higher levels of Ser1417-phosphorylated nNOSβ. Collectively, these data indicate that myofilament-associated nNOSβ predominantly regulates RV contractility through cTnI phosphorylation-mediated Ca2+ desensitization.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13637471/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149118609","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":"A hERG blocker facilitates K+ channel current by promoting pore opening while blocking.","authors":"Steffen S Docken, Matthew J Marquis, Khoa Ngo, Yuumu Wada, Satomi Kita, Vladimir Yarov-Yarovoy, Colleen E Clancy, Igor Vorobyov, Timothy J Lewis, Kazuharu Furutani, Jon T Sack","doi":"10.1085/jgp.202614015","DOIUrl":"10.1085/jgp.202614015","url":null,"abstract":"<p><p>Many drugs that block voltage-gated K+ channels encoded by the human ether-à-go-go-related gene (hERG) can cause long QT syndrome and life-threatening cardiac arrhythmias, yet the molecular mechanisms that determine this risk remain unclear. A process that may counteract arrhythmogenic hERG block, termed facilitation, is common to many clinically approved hERG blockers, including nifekalant, amiodarone, promethazine, imipramine, nortriptyline, haloperidol, verapamil, carvedilol, metoprolol, propranolol, quinidine, fluoxetine, and chlorpheniramine. Facilitation is an increase in hERG current, under certain conditions, due to these blockers. Here, we propose that an agonism-while-blocking mechanism underpins facilitation. We focus on nifekalant, a class III antiarrhythmic drug and exemplar hERG blocker that induces facilitation. We tested the hypothesis that nifekalant opens hERG channel gates while blocking, and that unblocking of these open-yet-blocked channels results in supranormal hERG current. We developed rate-theory kinetic models to identify features of agonism-while-blocking that produce facilitation. We generated atomistic models that predict that nifekalant blocks the hERG conduction path while modulating the intracellular conduction gate. Voltage-clamp measurements revealed that agonism-while-blocking can result in nifekalant block and facilitation. We speculate that this agonism-while-blocking mechanism contributes to the relative safety of hERG blockers that induce facilitation.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148834766","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":"Correction: Allosteric coupling in ligand-gated ion channels.","authors":"David Colquhoun, Remigijus Lape","doi":"10.1085/jgp.20121084408242026c","DOIUrl":"10.1085/jgp.20121084408242026c","url":null,"abstract":"","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13656842/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149168960","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":"State-dependent inhibition of LRRC8 volume-regulated anion channels by DCPIB.","authors":"Toshiki Yamada, Erkan Karakas, Jerod S Denton","doi":"10.1085/jgp.202614024","DOIUrl":"10.1085/jgp.202614024","url":null,"abstract":"<p><p>DCPIB is the prototypical inhibitor of leucine-rich repeat containing protein 8 volume-regulated anion channels (VRACs), yet the structural basis and state dependence of inhibition remain unclear. Here, we used chimeric channels, targeted mutagenesis, and electrophysiology to define the determinants of DCPIB inhibition and elucidate how drug binding is coupled to channel gating. Effective inhibition required coordinated contributions from extracellular loop 1 (EL1) and transmembrane domain 2 (TM2), which together form a functional module governing access to and stabilization of DCPIB-bound states. Within TM2, a single hydrophobic residue strongly influenced inhibition, indicating that subtle differences in helix packing shape drug sensitivity. Using the homo-heptameric 8C-8A(IL125) channel as a defined model, we found that DCPIB acts exclusively from the extracellular side, inhibits cooperatively, and enhances voltage-dependent inactivation. Mutational analysis showed that DCPIB interacts permissively with R103 of the outer constriction site (OCS) but does not depend on it for inhibition, suggesting that the inhibitor intercalates between subunits within a hydrophobic cleft to achieve stable pore engagement. Charged substitutions within TM2 provided functional evidence that DCPIB penetrates beyond the OCS. Mutations at positions implicated in lipid interactions markedly altered DCPIB efficacy without affecting volume sensitivity, indicating that productive drug-channel interactions, rather than lipid gating itself, are required for inhibition. Finally, charge neutralization on the conserved N-terminal constriction enhanced DCPIB sensitivity, supporting long-range coupling within the pore. Together, these results establish DCPIB as a state-dependent VRAC inhibitor that stabilizes an inactivated channel conformation and define mechanistic principles for the rational design of more potent and selective VRAC inhibitors.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13596092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149018869","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":"Early disruptions in brain capillary blood flow control in a mouse model of Alzheimer's disease.","authors":"Ashwini Hariharan, Abigail Vigderman, Dominic P Isaacs, Nick Weir, Gyubyung Park, Serena Edwards, Thomas A Longden","doi":"10.1085/jgp.202614014","DOIUrl":"10.1085/jgp.202614014","url":null,"abstract":"<p><p>In Alzheimer's disease (AD), vascular dysfunction and impaired control of brain blood flow can disrupt cellular bioenergetics decades before cognitive decline. Identifying the earliest vascular changes is therefore critical for developing therapies that intervene before the cascading events leading to neuronal decline. Brain energy supply is dynamically controlled by the cerebral vasculature, where capillary thin-strand pericytes are emerging as key players. We recently identified a central role for ATP-sensitive potassium (K+, KATP) channels in enabling thin-strand pericytes to sense local neuronal activity and generate hyperpolarizing signals that are transmitted via capillary endothelial cells to upstream arterioles, eliciting increases in blood flow. Importantly, thin-strand pericyte KATP channels are the centerpiece of an electro-metabolic \"energy switch\" mechanism that couples decreases in local glucose to hyperemia, providing a failsafe to ensure continual energy substrate supply to support neuronal function. Disruption of this mechanism could therefore precipitate an imbalance between demand and supply, creating an energy gap for neurons that leads to deleterious consequences. We demonstrate that capillary control of blood flow is disrupted in the early stages of disease progression in mice expressing familial AD mutations (5xFAD). Transgenic 5xFAD mice exhibit early disruption of capillary signaling, beginning with dysfunctional endothelial inward rectifier K+ (Kir)2.1 channels at 2-4 mo, disabling transmission of KATP-mediated signals to upstream blood flow control machinery, followed by direct impairment of pericyte KATP channel function by 6-8 mo. Together, these deficits cause early and sustained failure of electrical signaling from deep capillary pericytes to upstream arterioles and arteriole-capillary transition (ACT) zone vessels, limiting KATP-dependent energy-switch-mediated blood flow control. Our findings define a temporal and mechanistic framework linking familial AD mutations to early capillary signaling dysfunction and highlight preservation of capillary blood flow control as a potential therapeutic target to protect against downstream effects of amyloid β accumulation.</p>","PeriodicalId":54828,"journal":{"name":"Journal of General Physiology","volume":"158 6","pages":""},"PeriodicalIF":3.2,"publicationDate":"2026-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13671071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149197914","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}