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ATB0,+ (SLC6A14) is a member of the amino acid transporter branch of the SLC6 family along with GlyT1 (SLC6A9) and GlyT2 (SLC6A5), two glycine-specific transporters coupled to 2:1 and 3:1 Na⁺:Cl⁻, respectively. In contrast, ATB0,+ exhibits broad substrate specificity for all neutral and cationic amino acids, and its ionic coupling remains unsettled. Using the reversal potential slope method, we demonstrate a 3:1:1 Na⁺:Cl⁻:Gly stoichiometry for ATB0,+ that is consistent with its 2.1 e/Gly charge coupling. Like GlyT2, ATB0,+ behaves as a unidirectional transporter with virtually no glycine efflux at negative potentials after uptake, except by heteroexchange as remarkably shown by leucine activation of NMDARs in Xenopus oocytes coexpressing both membrane proteins. Analysis and computational modeling of the charge movement of ATB0,+ reveal a higher affinity for sodium in the absence of substrate than GlyT2 and a gating mechanism that locks Na⁺ into the apo-transporter at depolarized potentials. A 3:1 Na⁺:Cl⁻ stoichiometry justifies the concentrative transport properties of ATB0,+ and explains its trophic role in tumor growth, while rationalizing its phylogenetic proximity to GlyT2 despite their extreme divergence in specificity.

Ion concentration gradients across the cell membrane are fundamental to numerous processes that define life [...].Ion concentration gradients across the cell membrane are fundamental to numerous processes that define life [...].

ELIC channel structure Recently, the first crystal structure of a pentameric ligand-gated ion channel known as GLIC was published, which represented a closed state of the channel. Two papers in this issue report the crystal structures of the presumptive open states of a related channel — ELIC —and show significant tilting of the M2 and M3 α-helices from the closed state. Recently, the first crystal structure of a pentameric ligand-gated ion channel known as GLIC was published, which represented a closed state of the channel. In two papers in this issue, presumptive open states of a related channel — ELIC — have been crystallized and show significant tilting of the M2 and M3 α-helices from the closed state. The X-ray structure of a pentameric ligand-gated ion channel from Erwinia chrysanthemi (ELIC) has recently provided structural insight into this family of ion channels at high resolution 1 . The structure shows a homo-pentameric protein with a barrel-stave architecture that defines an ion-conduction pore located on the fivefold axis of symmetry. In this structure, the wide aqueous vestibule that is encircled by the extracellular ligand-binding domains of the five subunits narrows to a discontinuous pore that spans the lipid bilayer. The pore is constricted by bulky hydrophobic residues towards the extracellular side, which probably serve as barriers that prevent the diffusion of ions. This interrupted pore architecture in ELIC thus depicts a non-conducting conformation of a pentameric ligand-gated ion channel, the thermodynamically stable state in the absence of bound ligand. As ligand binding promotes pore opening in these ion channels and the specific ligand for ELIC has not yet been identified, we have turned our attention towards a homologous protein from the cyanobacterium Gloebacter violaceus (GLIC). GLIC was shown to form proton-gated channels that are activated by a pH decrease on the extracellular side and that do not desensitize after activation 2 . Both prokaryotic proteins, ELIC and GLIC form ion channels that are selective for cations over anions with poor discrimination among monovalent cations 1 , 2 , characteristics that resemble the conduction properties of the cation-selective branch of the family that includes acetylcholine and serotonin receptors 3 , 4 . Here we present the X-ray structure of GLIC at 3.1 Å resolution. The structure reveals a conformation of the channel that is distinct from ELIC and that probably resembles the open state. In combination, both structures suggest a novel gating mechanism for pentameric ligand-gated ion channels where channel opening proceeds by a change in the tilt of the pore-forming helices.

As a major proton-gated cation channel, acid-sensitive ion channels (ASICs) can perceive large extracellular pH changes. ASICs play an important role in the occurrence and development of diseases of various organs and tissues including in the heart, brain, and gastrointestinal tract, as well as in tumor proliferation, invasion, and metastasis in acidosis and regulation of an acidic microenvironment. The permeability of ASICs to sodium and calcium ions is the basis of their physiological and pathological roles in the body. This review summarizes the physiological and pathological mechanisms of ASICs in digestive system diseases, which plays an important role in the early diagnosis, treatment, and prognosis of digestive system diseases related to ASIC expression.

Parasitic diseases caused by protozoans are highly prevalent around the world, disproportionally affecting developing countries, where coinfection with other microorganisms is common. Control and treatment of parasitic infections are constrained by the lack of specific and effective drugs, plus the rapid emergence of resistance. Ion channels are main drug targets for numerous diseases, but their potential against protozoan parasites is still untapped. Ion channels are membrane proteins expressed in all types of cells, allowing for the flow of ions between compartments, and regulating cellular functions such as membrane potential, excitability, volume, signaling, and death. Channels and transporters reside at the interface between parasites and their hosts, controlling nutrient uptake, viability, replication, and infectivity. To understand how ion channels control protozoan parasites fate and to evaluate their suitability for therapeutics, we must deepen our knowledge of their structure, function, and modulation. However, methodological approaches commonly used in mammalian cells have proven difficult to apply in protozoans. This review focuses on ion channels described in protozoan parasites of clinical relevance, mainly apicomplexans and trypanosomatids, highlighting proteins for which molecular and functional evidence has been correlated with their physiological functions.

Fast inhibitory neurotransmission is essential for nervous system function and is mediated by binding of inhibitory neurotransmitters to receptors of the Cys-loop family embedded in the membranes of neurons. Neurotransmitter binding triggers a conformational change in the receptor, opening an intrinsic chloride channel and thereby dampening neuronal excitability. Here we present the first three-dimensional structure, to our knowledge, of an inhibitory anion-selective Cys-loop receptor, the homopentameric Caenorhabditis elegans glutamate-gated chloride channel α (GluCl), at 3.3 Å resolution. The X-ray structure of the GluCl–Fab complex was determined with the allosteric agonist ivermectin and in additional structures with the endogenous neurotransmitter l -glutamate and the open-channel blocker picrotoxin. Ivermectin, used to treat river blindness, binds in the transmembrane domain of the receptor and stabilizes an open-pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, and picrotoxin directly occludes the pore near its cytosolic base. GluCl provides a framework for understanding mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors. Structure of a key eukaryotic Cys-loop receptor The atomic resolution structure of the glutamate-gated chloride channel (GluCl) from Caenorhabditis elegans has been determined, in the presence of the allosteric agonist ivermectin, the endogenous neurotransmitter L-glutamate and the open-channel blocker picrotoxin. These structures provide a framework for understanding mechanisms of the fast inhibitory neurotransmission that is essential for nervous system function.

In 1987, two independent groups cloned a gene that encoded the potassium-ion-channel protein Shaker, enabling functional and structural studies that have transformed ion-channel research. Cloning of the Shaker protein had far-reaching effects in neuroscience.

Macrophages are the predominant component of innate immunity, which is an important protective barrier of our body. Macrophages are present in all organs and tissues of the body, their main functions include immune surveillance, bacterial killing, tissue remodeling and repair, and clearance of cell debris. In addition, macrophages can present antigens to T cells and facilitate inflammatory response by releasing cytokines. Macrophages are of high concern due to their crucial roles in multiple physiological processes. In recent years, new advances are emerging after great efforts have been made to explore the mechanisms of macrophage activation. Ion channel is a class of multimeric transmembrane protein that allows specific ions to go through cell membrane. The flow of ions through ion channel between inside and outside of cell membrane is required for maintaining cell morphology and intracellular signal transduction. Expressions of various ion channels in macrophages have been detected. The roles of ion channels in macrophage activation are gradually caught attention. K+ channels are the most studied channels in immune system. However, very few of published papers reviewed the studies of K+ channels on macrophages. Here, we will review the four types of K+ channels that are expressed in macrophages: voltage-gated K+ channel, calcium-activated K+ channel, inwardly rectifying K+ channel and two-pore domain K+ channel.

P2X receptor channels are trimeric ATP-activated ion channels expressed in neuronal and non-neuronal cells that are attractive therapeutic targets for human disorders. Seven subtypes of P2X receptor channels have been identified in mammals that can form both homomeric and heteromeric channels. P2X1–4 and P2X7 receptor channels are cation-selective, whereas P2X5 has been reported to have both cation and anion permeability. P2X receptor channel structures reveal that each subunit is comprised of two transmembrane helices, with both N-and C-termini on the intracellular side of the membrane and a large extracellular domain that contains the ATP binding sites at subunit interfaces. Recent structures of ATP-bound P2X receptors with the activation gate open reveal the unanticipated presence of a cytoplasmic cap over the central ion permeation pathway, leaving lateral fenestrations that may be largely buried within the membrane as potential pathways for ions to permeate the intracellular end of the pore. In the present study, we identify a critical residue within the intracellular lateral fenestrations that is readily accessible to thiol-reactive compounds from both sides of the membrane and where substitutions influence the relative permeability of the channel to cations and anions. Taken together, our results demonstrate that ions can enter or exit the internal pore through lateral fenestrations that play a critical role in determining the ion selectivity of P2X receptor channels.

The mechanism of selectivity in ion channels is still an open question in biology for more than half a century. Here, we suggest that quantum interference can be a solution to explain the selectivity mechanism in ion channels since interference happens between similar ions through the same size of ion channels. In this paper, we simulate two neighboring ion channels on a cell membrane with the famous double-slit experiment in physics to investigate whether there is any possibility of matter-wave interference of ions via movement through ion channels. Our obtained decoherence timescales indicate that the quantum states of ions can only survive for short times, i.e. ≈100 picoseconds in each channel and ≈17–53 picoseconds outside the channels, giving the result that the quantum interference of ions seems unlikely due to environmental decoherence. However, we discuss our results and raise few points, which increase the possibility of interference.