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Ion fluxes resolve organellar volume Animal cells continuously sample the surrounding medium, a feature accentuated in immune cells. Sampling is accomplished by trapping external medium into membrane-bound vesicles or vacuoles. These structures are promptly resolved, thus avoiding accumulation of endomembranes and volume expansion. In a variety of cultured cells, Freeman et al. found that this resolution entails conversion of spherical vacuoles into thin tubules, a process that involves marked changes in surface-to-volume ratio (see the Perspective by King and Smythe). Shrinkage of membrane-bound structures is driven by ion fluxes and subsequent osmotic transfer of water. Shriveled vacuoles attract curvature-sensing proteins that promote the extension of fine tubules. Ion channels thereby control membrane remodeling, enabling receptor recycling and proper routing of cellular cargo. Science , this issue p. 301 ; see also p. 246

Coupled transport Cation-chloride cotransporters move chloride and cations across the cell membrane and are important in regulating cell volume and setting the chloride concentration inside the cell. Mutations lead to serious diseases, such as epilepsy. Liu et al. present the structure of the human potassium-chloride cotransporter KCC1, as determined by cryo–electron microscopy. Based on the structure, functional studies, and molecular dynamics simulations, they propose an ion transport model. The structure provides a framework for interpreting disease-related mutations in potassium-chloride cotransporters. Science , this issue p. 505

The Moon's time-variable exosphere Earth's Moon does not have a conventional gaseous atmosphere, but instead an “exosphere” of particles ejected from the surface. Colaprete et al. have used NASA's LADEE orbiter to investigate how the exosphere varies over time, by using the glow from sodium and potassium atoms as a probe (see the Perspective by Dukes and Hurley). The exosphere composition varies by a factor of 2 to 3 over the course of a month, as different parts of the Moon are exposed to sunlight. There are also increases shortly after the Moon passes through streams of meteoroids. Science , this issue p. 249 ; see also p. 230

Structural Biology To make thyroid hormones, which are critical in development, iodine ions (I−) must be transported into thyroid cells. This is achieved by the sodium ion (Na+)/I− symporter (NIS), which couples the energetically unfavorable import of one I− with the energetically favorable import of two Na+. NIS also transports the environmental pollutant perchlorate (ClO4−), but in this case couples transport of one ClO4− with that of one Na+. Based on theory and experiments, Llorente-Esteban et al. show that ClO4− binds not only to the transport site but also to a nontransport site. Binding at the second site precludes binding of one of the Na+. Therefore, ClO4− not only inhibits I− transport by direct competition, it also reduces the driving force for I− transport by binding at the nontransport site. Nat. Struct. Mol. Biol. 27 , 533 (2020).

New sodium channel structures bound to toxins provide insight into voltage-gating mechanisms

We report that the addition of alkali ions (sodium or potassium) to gold on KLTL-zeolite and mesoporous MCM-41 silica stabilizes mononuclear gold in Au-O(OH) x -(Na or K) ensembles. This single-site gold species is active for the low-temperature (

Electrochemistry The so-called Birch reduction is frequently used by chemists despite its daunting conditions: Pyrophoric sodium is dissolved in pure liquified ammonia to achieve partial reduction of aromatics. Peters et al. surveyed and then optimized small-scale electrochemical alternatives to devise a safer protocol that can work on a larger scale with a broad range of functionally complex substrates. Science , this issue p. [838][1] [1]: /lookup/doi/10.1126/science.aav5606

Ion Channels In “excitable” cells, like neurons and muscle cells, a difference in electrical potential is used to transmit signals across the cell membrane. This difference is regulated by opening or closing ion channels in the cell membrane. For example, mutations in human voltage-gated sodium (Nav) channels are associated with disorders such as chronic pain, epilepsy, and cardiac arrhythmia. Pan et al. report the high-resolution structure of a human Nav channel, and Shen et al. report the structures of an insect Nav channel bound to the toxins that cause pufferfish and shellfish poisoning in humans. Together, the structures give insight into the molecular basis of sodium ion permeation and provide a path toward structure-based drug discovery. Science , this issue p. [eaau2486][1], p. [eaau2596][2] [1]: /lookup/doi/10.1126/science.aau2486 [2]: /lookup/doi/10.1126/science.aau2596

GPCR Close-Up Structures of G protein–coupled receptors (GPCRs) determined in the past few years, have provided insight into the function of this important family of membrane proteins. Liu et al. (p. 232 ) used a protein-engineering strategy to produce a stabilized version of the human A 2A adenosine receptor (A 2A AR). The high-resolution structure reveals the position of about 60 internal waters, which suggests an almost continuous channel in the GPCR and can explain the allosteric effects of Na + on ligand binding and how cholesterol may contribute to GPCR stabilization.

Setting Atoms Free In a plasma, gaseous atoms and molecules accumulate so much energy that they fall apart into electrons and all manner of bigger charged fragments. Free electrons can also wreak a degree of havoc within a liquid environment as they generate local reactive fragments, which then couple with the surrounding solvent to form a slew of products. Alexander et al. (p. 1072 ) explored what happens if reactive electrons emerged at the surface of such a liquid. To generate these conditions, they bombarded a shallow film of deuterated glycerol with sodium atoms that ionized on impact and discovered, in contrast with bulk liquid, that solvent-derived deuterium atoms escaped from the surface into the gas phase before they could react any further.

Maintaining Equilibrium Na + /Ca 2+ exchangers (NCX) are membrane transporters that maintain the homeostasis of cytosolic Ca 2+ and play an essential role in Ca 2+ signaling. Despite a long history of physiological work and a large body of functional data, the structural basis underlying the ion exchange mechanism of NCX is poorly understood. Liao et al. (p. 686 ; see the Perspective by Abramson et al. ) present a high-resolution crystal structure of an NCX from Methanococcus jannaschii and demonstrate that this archaeal NCX catalyzes Na + /Ca 2+ -exchange reactions similar to its eukaryotic counterpart. The structure clarifies the mechanism of ion exchange proteins and reveals the basis for the stoichiometry, cooperativity, and bidirectionality of the reaction.

MESSENGER's Third Set of Messages MESSENGER, the spacecraft en route to insertion into orbit about Mercury in March 2011, completed its third flyby of the planet on 29 September 2009. Prockter et al. (p. 668 , published online 15 July) present imaging data acquired during this flyby, showing that volcanism on Mercury has extended to much more recent times than previously assumed. The temporal extent of volcanic activity and, in particular, the timing of most recent activity had been missing ingredients in the understanding of Mercury's global thermal evolution. Slavin et al. (p. 665 , published online 15 July) report on magnetic field measurements made during the 29 September flyby, when Mercury's magnetosphere underwent extremely strong coupling with the solar wind. The planet's tail magnetic field increased and then decreased by factors of 2 to 3.5 during periods lasting 2 to 3 minutes. These observations suggest that magnetic open flux loads the magnetosphere, which is subsequently unloaded by substorms—magnetic disturbances during which energy is rapidly released in the magnetotail. At Earth, changes in tail magnetic field intensity during the loading/unloading cycle are much smaller and occur on much longer time scales. Vervack et al. (p. 672 , published online 15 July) used the Mercury Atmospheric and Surface Composition Spectrometer onboard MESSENGER to make measurements of Mercury's neutral and ion exospheres. Differences in the altitude profiles of magnesium, calcium, and sodium over the north and south poles of Mercury indicate that multiple processes are at play to create and maintain the exosphere.

Plant Science Salt stress in agriculture is not just a matter of being near the ocean; as much as half of irrigated farmland is overly salty. Plants have strategies to adjust to saline conditions, such as reducing sodium uptake or altering the architecture of their root systems. Julkowska et al. analyzed a range of Arabidopsis thaliana genotypes to identify genetic loci that could drive changes in root architecture in response to salt. Natural variation across 347 A. thaliana accessions affected the angle of roots and the distribution of bulk between main and lateral roots, leading to identification of the genes responsible. For example, variation in gene expression in response to salt showed that the CYP79B2 (cytochrome P450 family 79 subfamily B2) gene serves to reduce lateral root growth in salt-stressed conditions. Plant Cell 29 , 3198 (2017).

Croaking Frogs The global amphibian decline has been attributed, among other causes, to an amphibian skin disease chytridiomycosis caused by the fungus Batrachochytrium dendrobatidis . However, how this pathogen causes mortality has been unclear. Voyles et al. (p. 582 ) show that this superficial skin infection may lead to cardiac failure owing to changes caused by lowered ion transport through the skin and consequent electrolyte reduction in the blood.

APC Transporter Structure Amino acid, polyamine, and organocation (APC) transporters that move a range of organic molecules across the cell membrane are important in many cellular processes. Shaffer et al. (p. 1010 ; published online 16 July) report the crystal structure of apoApcT, a proton-dependent APC transporter. The structure shows similarity to the sodium-coupled amino acid transporter LeuT and has an amino group from a lysine in an equivalent position to a sodium ion in LeuT. This suggests common principles between proton- and sodium-coupled transporters.

MESSENGER from Mercury The spacecraft MESSENGER passed by Mercury in October 2008, in what was the second of three fly-bys before it settles into the planet's orbit in 2011. Another spacecraft visited Mercury in the mid-1970s, which mapped 45% of the planet's surface. Now, after MESSENGER, only 10% of Mercury's surface remains to be imaged up close. Denevi et al. (p. 613 ) use this near-global data to look at the mechanisms that shaped Mercury's crust, which likely formed by eruption of magmas of different compositions over a long period of time. Like the Moon, Mercury's surface is dotted with impact craters. Watters et al. (p. 618 ) describe a well-preserved impact basin, Rembrandt, which is second in size to the largest known basin, Caloris. Unlike Caloris, Rembrandt is not completely filled by material of volcanic origin, preserving clues to its formation and evolution. It displays unique patterns of tectonic deformation, some of which result from Mercury's contraction as its interior cooled over time. Mercury's exosphere and magnetosphere were also observed (see the Perspective by Glassmeier ). Magnetic reconnection is a process whereby the interplanetary magnetic field lines join the magnetospheric field lines and transfer energy from the solar wind into the magnetosphere. Slavin et al. (p. 606 ) report observations of intense magnetic reconnection 10 times as intense as that of Earth. McClintock et al. (p. 610 ) describe simultaneous, high-resolution measurements of Mg, Ca, and Na in Mercury's exosphere, which may shed light on the processes that create and maintain the exosphere.

Secondary transporters are workhorses of cellular membranes, catalyzing the movement of small molecules and ions across the bilayer and coupling substrate passage to ion gradients. However, the conformational changes that accompany substrate transport, the mechanism by which a substrate moves through the transporter, and principles of competitive inhibition remain unclear. We used crystallographic and functional studies on the leucine transporter (LeuT), a model for neurotransmitter sodium symporters, to show that various amino acid substrates induce the same occluded conformational state and that a competitive inhibitor, tryptophan (Trp), traps LeuT in an open-to-out conformation. In the Trp complex, the extracellular gate residues arginine 30 and aspartic acid 404 define a second weak binding site for substrates or inhibitors as they permeate from the extracellular solution to the primary substrate site, which demonstrates how residues that participate in gating also mediate permeation.

Sodium exhibits a pronounced minimum of the melting temperature at ∼118 gigapascals and 300 kelvin. Using single-crystal high-pressure diffraction techniques, we found that the minimum of the sodium melting curve is associated with a concentration of seven different crystalline phases. Slight changes in pressure and/or temperature induce transitions between numerous structural modifications, several of which are highly complex. The complexity of the phase behavior above 100 gigapascals suggests extraordinary liquid and solid states of sodium at extreme conditions and has implications for other seemingly simple metals.

Focal and segmental glomerulosclerosis (FSGS) is a kidney disorder of unknown etiology, and up to 20% of patients on dialysis have been diagnosed with it. Here we show that a large family with hereditary FSGS carries a missense mutation in the TRPC6 gene on chromosome 11q, encoding the ion-channel protein transient receptor potential cation channel 6 (TRPC6). The proline-to-glutamine substitution at position 112, which occurs in a highly conserved region of the protein, enhances TRPC6-mediated calcium signals in response to agonists such as angiotensin II and appears to alter the intracellular distribution of TRPC6 protein. Previous work has emphasized the importance of cytoskeletal and structural proteins in proteinuric kidney diseases. Our findings suggest an alternative mechanism for the pathogenesis of glomerular disease.

TRPM4 has recently been described as a calcium-activated nonselective (CAN) cation channel that mediates membrane depolarization. However, the functional importance of TRPM4 in the context of calcium (Ca 2+ ) signaling and its effect on cellular responses are not known. Here, the molecular inhibition of endogenous TRPM4 in T cells was shown to suppress TRPM4 currents, with a profound influence on receptor-mediated Ca 2+ mobilization. Agonist-mediated oscillations in intracellular Ca 2+ concentration ([Ca 2+ ] i ), which are driven by store-operated Ca 2+ influx, were transformed into a sustained elevation in [Ca 2+ ] i . This increase in Ca 2+ influx enhanced interleukin-2 production. Thus, TRPM4-mediated depolarization modulates Ca 2+ oscillations, with downstream effects on cytokine production in T lymphocytes.

Synapses in the central nervous system are usually defined by presynaptic exocytotic release sites and postsynaptic differentiations. We report here a demonstration of dendrodendritic inhibition that does not engage a conventional synapse. Using amperometric and patch-clamp recordings in rat brain slices of the substantia nigra, we found that blockade of the dopamine transporter abolished the dendritic release of dopamine and the resulting self-inhibition. These findings demonstrate that dendrodendritic autoinhibition entails the carrier-mediated release of dopamine rather than conventional exocytosis. This suggests that some widely used antidepressants that inhibit the dopamine transporter may benefit patients in the early stages of Parkinson's disease.

The region around Mercury is filled with ions that originate from interactions of the solar wind with Mercury's space environment and through ionization of its exosphere. The MESSENGER spacecraft's observations of Mercury's ionized exosphere during its first flyby yielded Na + , O + , and K + abundances, consistent with expectations from observations of neutral species. There are increases in ions at a mass per charge ( m / q ) = 32 to 35, which we interpret to be S + and H 2 S + , with (S + + H 2 S + )/(Na + + Mg + ) = 0.67 ± 0.06, and from water-group ions around m / q = 18, at an abundance of 0.20 ± 0.03 relative to Na + plus Mg + . The fluxes of Na + , O + , and heavier ions are largest near the planet, but these Mercury-derived ions fill the magnetosphere. Doubly ionized ions originating from Mercury imply that electrons with energies less than 1 kiloelectron volt are substantially energized in Mercury's magnetosphere.

A 6-month-long monitoring campaign of the Io plasma torus and neutral cloud was conducted to determine the characteristics of their interaction. During the observations, a large outburst of material from Io—inferred to be caused by the eruption of a volcanic plume on Io—caused a transient increase in the neutral cloud and plasma torus masses. The response of the plasma torus to this outburst shows that the interaction between Io and Jupiter's magnetosphere is stabilized by a feedback mechanism in which increases in the plasma torus mass cause a nonlinear increase in loss from the plasma torus, limiting plasma buildup.

Sodium (Na+) at high millimolar concentrations in soils is toxic to most higher plants and severely reduces agricultural production worldwide. However, the molecular mechanisms for plant Na+ uptake remain unknown. Here, the wheat root high-affinity potassium (K+) uptake transporter HKT1 was shown to function as a high-affinity K(+)-Na+ cotransporter. High-affinity K+ uptake was activated by micromolar Na+ concentrations; moreover, high-affinity Na+ uptake was activated by K+ (half-activation constant, 2.8 microM K+). However, at physiologically detrimental concentrations of Na+, K+ accumulation mediated by HKT1 was blocked and low-affinity Na+ uptake occurred (Michaelis constant, approximately 16 mM Na+), which correlated to Na+ toxicity in plants. Point mutations in the sixth putative transmembrane domain of HKT1 that increase Na+ tolerance were isolated with the use of yeast as a screening system. Na+ uptake and Na+ inhibition of K+ accumulation indicate a possible role for HKT1 in physiological Na+ toxicity in plants.

Cystic fibrosis transmembrane regulator (CFTR), the gene product that is mutated in cystic fibrosis (CF) patients, has a well-recognized function as a cyclic adenosine 3',5'-monophosphate (cAMP)-regulated chloride channel, but this property does not account for the abnormally high basal rate and cAMP sensitivity of sodium ion absorption in CF airway epithelia. Expression of complementary DNAs for rat epithelial Na+ channel (rENaC) alone in Madin Darby canine kidney (MDCK) epithelial cells generated large amiloride-sensitive sodium currents that were stimulated by cAMP, whereas coexpression of human CFTR with rENaC generated smaller basal sodium currents that were inhibited by cAMP. Parallel studies that measured regulation of sodium permeability in fibroblasts showed similar results. In CF airway epithelia, the absence of this second function of CFTR as a cAMP-dependent regulator likely accounts for abnormal sodium transport.

The functional consequences of single proton transfers occurring in the pore of a cyclic nucleotide-gated channel were observed with patch recording techniques. These results led to three conclusions about the chemical nature of ion binding sites in the conduction pathway: The channel contains two identical titratable sites, even though there are more than two (probably four) identical subunits; the sites are formed by glutamate residues that have a pKa (where K(a) is the acid constant) of 7.6; and protonation of one site does not perturb the pKa of the other. These properties point to an unusual arrangement of carboxyl side-chain residues in the pore of a cation channel.

In cystic fibrosis (CF), absence or dysfunction of a phosphorylation-regulated chloride channel [CF transmembrane conductance regulator (CFTR)] leads to the loss or reduction of chloride secretion into the airways. Active sodium absorption is also increased in CF, and both of these ion transport changes could alter fluid transport across the airways. Under baseline conditions, cultured human airway epithelia from normal individuals absorbed fluid, and this absorption was increased in epithelia from patients with CF. In normal and CF epithelial cultures fluid absorption was inhibited by amiloride. Adenosine 3',5'-monophosphate stimulated fluid secretion in normal epithelial cultures but not in cultures from individuals with CF. In contrast, fluid secretion induced by nucleotide triphosphates (uridine triphosphate or adenosine triphosphate) was unaltered in cultures of epithelia from patients with CF, suggesting an approach to the treatment of CF.

The function of voltage-gated sodium channels that are responsible for action potential generation in mammalian brain neurons is modulated by phosphorylation by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase (cA-PK) and by protein kinase C (PKC). Reduction of peak sodium currents by cA-PK in intact cells required concurrent activation of PKC and was prevented by blocking phosphorylation of serine 1506, a site in the inactivation gate of the channel that is phosphorylated by PKC but not by cA-PK. Replacement of serine 1506 with negatively charged amino acids mimicked the effect of phosphorylation. Conversion of the consensus sequence surrounding serine 1506 to one more favorable for cA-PK enhanced modulation of sodium currents by cA-PK. Convergent modulation of sodium channels required phosphorylation of serine 1506 by PKC accompanied by phosphorylation of additional sites by cA-PK. This regulatory mechanism may serve to integrate neuronal signals mediated through these parallel signaling pathways.

Hemodynamic shear stress affects endothelial cell structure and function, but little is known about the signal transduction mechanisms involved in these processes. The effect of laminar shear stress on cytosolic pH (pHi) was examined in rat aortic endothelial cells cultured in glass capillary tubes. Shear stress forces led to a rapid decrease in pHi (maximal effect 0.09 pH unit at 13.4 dynes per square centimeter). Removal of specific ions or addition of exchange inhibitors suggests that in vascular endothelial cells shear stress forces activate both an alkali extruder, sodium ion-independent chloride-bicarbonate ion exchange, and an acid extruder, sodium-hydrogen ion exchange; the net effect in physiologic buffer with the bicarbonate ion is a decrease in pHi.