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Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of physiological functions such as blood pressure regulation 1 , apoptotic cell clearance 2 and human oocyte development 3 . Here we present several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 angström, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. We reveal a gating mechanism that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. We identified a carbenoxolone-binding site embraced by W74 in the extracellular entrance and a role for carbenoxolone as a channel blocker. We identified a gap-junction-like structure using a glycosylation-deficient mutant, N255A. Our studies provide a solid foundation for understanding the molecular mechanisms underlying the channel gating and inhibition of PANX1 and related large-pore channels. Cryo-electron microscopy structures of the ATP-permeable channel pannexin 1 reveal a gating mechanism involving multiple distinct ion-conducting pathways.

The Ca 2+ -activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca 2+ regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca 2+ -bound open state, and an antagonist-bound inhibited state. We define two novel ligand binding sites: a Ca 2+ site (Ca ICD ) in the intracellular domain and an antagonist site in the transmembrane domain (TMD). The Ca ICD site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca 2+ binding to the Ca TMD site, which is conserved throughout TRPM channels. Conformational changes initialized from both Ca 2+ sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1–S4 domain and pore domain, stabilizing the transmembrane domain in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents. Cryo-EM structures of zebrafish TRPM5 reveal closed and Ca 2+ -bound open states, a unique Ca 2+ binding site that modulates voltage sensitivity and the mechanism of antagonist action.

Protein phosphorylation is one of the major molecular mechanisms regulating protein activity and function throughout the cell. Pannexin 1 (PANX1) is a large-pore channel permeable to ATP and other cellular metabolites. Its tyrosine phosphorylation and subsequent activation have been found to play critical roles in diverse cellular conditions, including neuronal cell death, acute inflammation, and smooth muscle contraction. Specifically, the non-receptor kinase Src has been reported to phosphorylate Tyr198 and Tyr308 of mouse PANX1 (equivalent to Tyr199 and Tyr309 of human PANX1), resulting in channel opening and ATP release. Although the Src-dependent PANX1 activation mechanism has been widely discussed in the literature, independent validation of the tyrosine phosphorylation of PANX1 has been lacking. Here, we show that commercially available antibodies against the two phosphorylation sites mentioned above—which were used to identify endogenous PANX1 phosphorylation at these two sites—are nonspecific and should not be used to interpret results related to PANX1 phosphorylation. We further provide evidence that neither tyrosine residue is a major phosphorylation site for Src kinase in heterologous expression systems. We call on the field to re-examine the existing paradigm of tyrosine phosphorylation-dependent activation of the PANX1 channel.

The proton-activated chloride channel (PAC) is active across a wide range of mammalian cells and is involved in acid-induced cell death and tissue injury 1 – 3 . PAC has recently been shown to represent a novel and evolutionarily conserved protein family 4 , 5 . Here we present two cryo-electron microscopy structures of human PAC in a high-pH resting closed state and a low-pH proton-bound non-conducting state. PAC is a trimer in which each subunit consists of a transmembrane domain (TMD), which is formed of two helices (TM1 and TM2), and an extracellular domain (ECD). Upon a decrease of pH from 8 to 4, we observed marked conformational changes in the ECD–TMD interface and the TMD. The rearrangement of the ECD–TMD interface is characterized by the movement of the histidine 98 residue, which is, after acidification, decoupled from the resting position and inserted into an acidic pocket that is about 5 Å away. Within the TMD, TM1 undergoes a rotational movement, switching its interaction partner from its cognate TM2 to the adjacent TM2. The anion selectivity of PAC is determined by the positively charged lysine 319 residue on TM2, and replacing lysine 319 with a glutamate residue converts PAC to a cation-selective channel. Our data provide a glimpse of the molecular assembly of PAC, and a basis for understanding the mechanism of proton-dependent activation. Cryo-electron microscopy structures of the human proton-activated chloride channel (PAC) shed light on its pH-dependent gating mechanism and anion selectivity.

Due to their safety and effectiveness, bioactive compounds and nutrient interventions are widely considered beneficial for treating these diseases (26,27). [...]it is important to summarize the recent advancements in the associations among bioactive compounds, nutrients, gut microbiota, and human health, demonstrating the significance of these interconnected factors in maintaining physiological balance and preventing disease, shaping therapeutic strategies, elucidating the underlying mechanisms that drive health and disease, and developing targeted nutritional and biomedical interventions. The authors identified the following limitations and proposed potential solutions. Since HZ primarily affects elderly populations with weakened cell-mediated immunity (29,30), future experiments should include aged mouse models. [...]because varicella zoster virus (VZV) is highly species-specific and causes clinical symptoms only in humans and non-human primates, murine models cannot support viral latency or reactivation (31). [...]thorough efficacy assessment in rhesus macaque models is a crucial step in preclinical development.

Proton-activated chloride (PAC) channel is a ubiquitously expressed pH-sensing ion channel, encoded by PACC1 ( TMEM206 ). PAC regulates endosomal acidification and macropinosome shrinkage by releasing chloride from the organelle lumens. It is also found at the cell surface, where it is activated under pathological conditions related to acidosis and contributes to acid-induced cell death. However, the pharmacology of the PAC channel is poorly understood. Here, we report that phosphatidylinositol (4,5)-bisphosphate (PIP 2 ) potently inhibits PAC channel activity. We solved the cryo-electron microscopy structure of PAC with PIP 2 at pH 4.0 and identified its putative binding site, which, surprisingly, locates on the extracellular side of the transmembrane domain (TMD). While the overall conformation resembles the previously resolved PAC structure in the desensitized state, the TMD undergoes remodeling upon PIP 2 -binding. Structural and electrophysiological analyses suggest that PIP 2 inhibits the PAC channel by stabilizing the channel in a desensitized-like conformation. Our findings identify PIP 2 as a new pharmacological tool for the PAC channel and lay the foundation for future drug discovery targeting this channel.

Gannan navel orange and Jinggang pomelo, belonging to the genus Citrus, are good sources of phenolic compounds, which are mainly concentrated in the peel. These phenolic compounds are considered promising in the prevention and treatment of non-alcoholic fatty liver disease (NAFLD). In order to maximize nutrients retention and bioactivity in the peel, pomelo peel and orange peel were processed using freeze-drying technology and mixed in the ratio (pomelo peel powder 50% and orange peel powder 50%) to make citrus peel powder (CPP). The purpose of this study was to explore new strategies and mechanisms associated with the consumption of CPP to alleviate nonalcoholic fatty liver injury, lipid metabolism disorders, and gut microbiota dysbiosis in obese mice induced by high-fat diet (HFD). The results showed that after 12 weeks of CPP administration, CPP supplementation had a strong inhibitory effect on HFD-induced weight gain, hepatic fat accumulation, dyslipidemia, and the release of pro-inflammatory cytokines. In particular, CPP modulates the composition of the intestinal flora, such as increasing the relative abundance of phylum Firmicutes, genus Faecalibaculum, genus Lactobacillus, genus Dubosiella, and genus Lachnospiraceae_NK4A136_ group and decreasing the relative abundance of phylum Bacteroidota, genus Helicobacter, and genus Bacteroides. These results suggest that CPP has a preventive effect on NAFLD, which can be related to the regulation of intestinal flora.

During the presummer rainy season (April–June), southern China often experiences frequent occurrences of extreme rainfall, leading to severe flooding and inundations. To expedite the efforts in improving the quantitative precipitation forecast (QPF) of the presummer rainy season rainfall, the China Meteorological Administration (CMA) initiated a nationally coordinated research project, namely, the Southern China Monsoon Rainfall Experiment (SCMREX) that was endorsed by the World Meteorological Organization (WMO) as a research and development project (RDP) of the World Weather Research Programme (WWRP). The SCMREX RDP (2013–18) consists of four major components: field campaign, database management, studies on physical mechanisms of heavy rainfall events, and convection-permitting numerical experiments including impact of data assimilation, evaluation/improvement of model physics, and ensemble prediction. The pilot field campaigns were carried out from early May to mid-June of 2013–15. This paper: i) describes the scientific objectives, pilot field campaigns, and data sharing of SCMREX; ii) provides an overview of heavy rainfall events during the SCMREX-2014 intensive observing period; and iii) presents examples of preliminary research results and explains future research opportunities.

Purinergic signaling relies on ATP release through exocytosis and large-pore channels. Large-pore channels permeate both small anions like chloride and large signaling molecules like ATP, but how this broad cargo selectivity is structurally controlled remains elusive. Here we investigate PANX1, a prototypical large-pore channel, and uncover structural plasticity at the extracellular entrance formed by seven tryptophan (W74) residues. The W74 sidechains are flexible, sampling conformations that range from a constricted state permissive only to chloride to a dilated state compatible with ATP. These states are coupled to variable cation–π interactions between W74 and arginine 75 (R75), suggesting a mechanism for dynamic tuning of pore architecture and selective cargo permeation. We also identify mefloquine as a positive modulator of PANX1 that binds near the side tunnel to control ion flow through this pathway. Together, these findings define the structural principles underlying PANX1 permeation and modulation. ATP release through large-pore channels is essential for cell communication. Here, the authors reveal how structural flexibility in the PANX1 pore enables selective passage of molecules like ATP and identify mefloquine as a positive modulator acting through a newly identified binding site.

In response to acidic pH, the widely expressed proton-activated chloride (PAC) channel opens and conducts anions across cellular membranes. By doing so, PAC plays an important role in both cellular physiology (endosome acidification) and diseases associated with tissue acidosis (acid-induced cell death). Despite the available structural information, how proton binding in the extracellular domain (ECD) leads to PAC channel opening remains largely unknown. Here, through comprehensive mutagenesis and electrophysiological studies, we identified several critical titratable residues, including two histidine residues (H130 and H131) and an aspartic acid residue (D269) at the distal end of the ECD, together with the previously characterized H98 at the transmembrane domain–ECD interface, as potential pH sensors for human PAC. Mutations of these residues resulted in significant changes in pH sensitivity. Some combined mutants also exhibited large basal PAC channel activities at neutral pH. By combining molecular dynamics simulations with structural and functional analysis, we further found that the β12 strand at the intersubunit interface and the associated “joint region” connecting the upper and lower ECDs allosterically regulate the proton-dependent PAC activation. Our studies suggest a distinct pH-sensing and gating mechanism of this new family of ion channels sensitive to acidic environment.