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Voltage-gated sodium channels located in axon initial segments (AIS) trigger action potentials (AP) and play pivotal roles in the excitability of cortical pyramidal neurons. The differential electrophysiological properties and distributions of NaV1.2 and NaV1.6 channels lead to distinct contributions to AP initiation and propagation. While NaV1.6 at the distal AIS promotes AP initiation and forward propagation, NaV1.2 at the proximal AIS promotes the backpropagation of APs to the soma. Here, we show the small ubiquitin-like modifier (SUMO) pathway modulates Na+ channels at the AIS to increase neuronal gain and the speed of backpropagation. Since SUMO does not affect NaV1.6, these effects were attributed to SUMOylation of NaV1.2. Moreover, SUMO effects were absent in a mouse engineered to express NaV1.2-Lys38Gln channels that lack the site for SUMO linkage. Thus, SUMOylation of NaV1.2 exclusively controls INaP generation and AP backpropagation, thereby playing a prominent role in synaptic integration and plasticity.

TOKs are outwardly rectifying K+ channels in fungi with two pore-loops and eight transmembrane spans. Here, we describe the TOKs from four pathogens that cause the majority of life-threatening fungal infections in humans. These TOKs pass large currents only in the outward direction like the canonical isolate from Saccharomyces cerevisiae (ScTOK), and distinct from other K+ channels. ScTOK, AfTOK1 (Aspergillus fumigatus), and H99TOK (Cryptococcus neoformans grubii) are K+ -selective and pass current above the K+ reversal potential. CaTOK (Candida albicans) and CnTOK (Cryptococcus neoformans neoformans) pass both K+ and Na+ and conduct above a reversal potential reflecting the mixed permeability of their selectivity filter. Mutations in CaTOK and ScTOK at sites homologous to those that open the internal gates in classical K+ channels are shown to produce inward TOK currents. A favored model for outward rectification is proposed whereby the reversal potential determines ion occupancy, and thus, conductivity, of the selectivity filter gate that is coupled to an imperfectly restrictive internal gate, permitting the filter to sample ion concentrations on both sides of the membrane.

Research into non-hormonal, alternative therapies is necessary for women for whom menopausal hormone therapy is contraindicated or for women who do not wish to take hormones. This review focuses on one such non-hormonal option, namely, purified and specific cytoplasmic pollen extract, or PureCyTonin®. This extract has been evaluated in several preclinical and clinical studies, where it demonstrated its value as a safe and non-estrogenic alternative for menopause. This review presents the beneficial effects of PureCyTonin® in the treatment of menopausal symptoms (e.g. hot flushes) in healthy women, as well as in premenstrual syndrome. We discuss the mechanism of action of PureCyTonin®, an SSRI-'like' therapy. The lack of estrogenic effect demonstrated in preclinical studies suggests that PureCyTonin® may also be a suitable option for the management of menopausal symptoms in women with breast cancer.

Using a de novo peptide inhibitor, Corza6 (C6), we demonstrate that the human voltage-gated proton channel (hHv1) is the main pathway for H+ efflux that allows capacitation in sperm and permits sustained reactive oxygen species (ROS) production in white blood cells (WBCs). C6 was identified by a phage-display strategy whereby ∼1 million novel peptides were fabricated on an inhibitor cysteine knot (ICK) scaffold and sorting on purified hHv1 protein. Two C6 peptides bind to each dimeric channel, one on the S3-S4 loop of each voltage sensor domain (VSD). Binding is cooperative with an equilibrium affinity (Kd) of ∼1 nM at -50 mV. As expected for a VSD-directed toxin, C6 inhibits by shifting hHv1 activation to more positive voltages, slowing opening and speeding closure, effects that diminish with membrane depolarization.

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In order to multiply and cause disease a virus must transport its genome from outside the cell into the cytosol, most commonly achieved through the endocytic network. Endosomes transport virus particles to specific cellular destinations and viruses exploit the changing environment of maturing endocytic vesicles as triggers to mediate genome release. Previously we demonstrated that several bunyaviruses, which comprise the largest family of negative sense RNA viruses, require the activity of cellular potassium (K+) channels to cause productive infection. Specifically, we demonstrated a surprising role for K+ channels during virus endosomal trafficking. In this study, we have used the prototype bunyavirus, Bunyamwera virus (BUNV), as a tool to understand why K+ channels are required for progression of these viruses through the endocytic network. We report three major findings: First, the production of a dual fluorescently labelled bunyavirus to visualize virus trafficking in live cells. Second, we show that BUNV traffics through endosomes containing high [K+] and that these K+ ions influence the infectivity of virions. Third, we show that K+ channel inhibition can alter the distribution of K+ across the endosomal system and arrest virus trafficking in endosomes. These data suggest high endosomal [K+] is a critical cue that is required for virus infection, and is controlled by cellular K+ channels resident within the endosome network. This highlights cellular K+ channels as druggable targets to impede virus entry, infection and disease.

IKs channels open in response to depolarization of the membrane voltage during the cardiac action potential, passing potassium ions outward to repolarize ventricular myocytes and end each beat. Here, we show that the voltage required to activate IKs channels depends on their covalent modification by small ubiquitin-like modifier (SUMO) proteins. IKs channels are comprised of four KCNQ1 pore-forming subunits, two KCNE1 accessory subunits, and up to four SUMOs, one on Lys424 of each KCNQ1 subunit. Each SUMO shifts the half-maximal activation voltage (V1/2) of IKs ∼ +8 mV, producing a maximal +34-mV shift in neonatal mouse cardiac myocytes or Chinese hamster ovary (CHO) cells expressing the mouse or human subunits. Unexpectedly, channels formed without KCNE1 carry at most two SUMOs despite having four available KCNQ1-Lys424 sites. SUMOylation of KCNQ1 is KCNE1 dependent and determines the native attributes of cardiac IKs in vivo.

In this issue of EMBO Molecular Medicine, Decher et al (2017) identify a point mutation in the K2P2 (TREK‐1) potassium (K+) channel that changes function in just those ways expected to predispose to right ventricular outflow tract (RVOT) ventricular tachycardia (VT) in the patient they study. Whereas wild‐type channels are selective for K+ and inhibited by β‐adrenergic stimulation, mutant I267T channels pass sodium (Na+) into the cells, even during β‐adrenergic stimulation, and are more active in response to membrane stretch, changes predicted to enhance cardiac myocyte excitability. The report contributes to accumulating evidence for Na+ leak via K2P channels in association with normal development (Thomas et al, 2008), acquired arrhythmia (Ma et al, 2011), and now a missense mutation. Decher et al (2017) both inform and direct us toward interesting opportunities for further investigation.

The mechanism for the earliest response of central neurons to hypoxia-an increase in voltage-gated sodium current (INa)-has been unknown. Here, we show that hypoxia activates the Small Ubiquitin-like Modifier (SUMO) pathway in rat cerebellar granule neurons (CGN) and that SUMOylation of NaV1.2 channels increases INa. The time-course for SUMOylation of single NaV1.2 channels at the cell surface and changes in INa coincide, and both are prevented by mutation of NaV1.2-Lys38 or application of a deSUMOylating enzyme. Within 40 s, hypoxia-induced linkage of SUMO1 to the channels is complete, shifting the voltage-dependence of channel activation so that depolarizing steps evoke larger sodium currents. Given the recognized role of INa in hypoxic brain damage, the SUMO pathway and NaV1.2 are identified as potential targets for neuroprotective interventions.

Disentangling inputs of aeolian dust, ice-rafted debris (IRD), and eroded continental detritus delivered by ocean currents to marine sediments provide important insights into Earth System processes and climate. This study uses Sr-Nd-Pb isotope ratios of the continent-derived (lithogenic) fraction in deep-sea core TN057-6 from the subantarctic Southern Ocean southwest of Africa over the past 150,000 y to identify source regions and quantify their relative contributions and fluxes utilizing a mixing model set in a Bayesian framework. The data are compared with proxies from parallel core Ocean Drilling Program Site 1090 and newly presented data from potential South America aeolian dust source areas (PSAs), allowing for an integrated investigation into atmospheric, oceanic, and cryospheric dynamics. PSA inputs varied on glacial/interglacial timescales, with southern South American sources dominating up to 88% of the lithogenic fraction (mainly Patagonia, which provided up to 68%) during cold periods, while southern African sources were more important during interglacials. During the warmer Marine Isotope Stage (MIS) 3 of the last glacial period, lithogenic fluxes were twice that of colder MIS2 and MIS4 at times, and showed unique isotope ratios best explained by Antarctic-derived IRD, likely from the Weddell Sea. The IRD intrusions contributed up to 41% at times and followed Antarctic millennial warming events that raised temperatures, causing instability of icesheet margins. High IRD was synchronous with increased bioavailable iron, nutrient utilization, high biological productivity, and decreased atmospheric CO2. Overall, TN057-6 sediments record systematic Southern Hemisphere climate shifts and cryospheric changes that impacted biogeochemical cycling on both glacial/interglacial and subglacial timescales. [ABSTRACT FROM AUTHOR]

The histories of African crops remain poorly understood despite their contemporary importance. Integration of crops from western, eastern and northern Africa probably first occurred in the Great Lakes Region of eastern Africa; however, little is known about when and how these agricultural systems coalesced. This article presents archaeobotanical analyses from an approximately 9000-year archaeological sequence at Kakapel Rockshelter in western Kenya, comprising the largest and most extensively dated archaeobotanical record from the interior of equatorial eastern Africa. Direct radiocarbon dates on carbonized seeds document the presence of the West African crop cowpea (Vigna unguiculata (L.) Walp) approximately 2300 years ago, synchronic with the earliest date for domesticated cattle (Bos taurus). Peas (Pisum sativum L. or Pisum abyssinicum A. Braun) and sorghum (Sorghum bicolor (L.) Moench) from the northeast and eastern African finger millet (Eleusine coracana (L.) Gaertn.) are incorporated later, by at least 1000 years ago. Combined with ancient DNA evidence from Kakapel and the surrounding region, these data support a scenario in which the use of diverse domesticated species in eastern Africa changed over time rather than arriving and being maintained as a single package. Findings highlight the importance of local heterogeneity in shaping the spread of food production in sub-Saharan Africa. [ABSTRACT FROM AUTHOR]