Mg2+ Enhances Voltage Sensor/Gate Coupling in BK Channels

BK (Slo1) potassium channels are activated by millimolar intracellular Mg2+ as well as micromolar Ca2+ and membrane depolarization. Mg2+ and Ca2+ act in an approximately additive manner at different binding sites to shift the conductance–voltage (GK-V) relation, suggesting that these ligands might work through functionally similar but independent mechanisms. However, we find that the mechanism of Mg2+ action is highly dependent on voltage sensor activation and therefore differs fundamentally from that of Ca2+. Evidence that Ca2+ acts independently of voltage sensor activation includes an ability to increase open probability (PO) at extreme negative voltages where voltage sensors are in the resting state; 2 μM Ca2+ increases PO more than 15-fold at −120 mV. However 10 mM Mg2+, which has an effect on the GK-V relation similar to 2 μM Ca2+, has no detectable effect on PO when voltage sensors are in the resting state. Gating currents are only slightly altered by Mg2+ when channels are closed, indicating that Mg2+ does not act merely to promote voltage sensor activation. Indeed, channel opening is facilitated in a voltage-independent manner by Mg2+ in a mutant (R210C) whose voltage sensors are constitutively activated. Thus, 10 mM Mg2+ increases PO only when voltage sensors are activated, effectively strengthening the allosteric coupling of voltage sensor activation to channel opening. Increasing Mg2+ from 10 to 100 mM, to occupy very low affinity binding sites, has additional effects on gating that more closely resemble those of Ca2+. The effects of Mg2+ on steady-state activation and IK kinetics are discussed in terms of an allosteric gating scheme and the state-dependent interactions between Mg2+ and voltage sensor that may underlie this mechanism

A Network-based Approach to Mining Competitor Relationships from Online News

Identifying competitors for an individual company or a group of companies is important for businesses. Although people can consult paid company profile resources such as Hoover’s and Mergent, these sources are incomplete in company relationship coverage. We present an approach that uses graph-theoretic measures and machine learning techniques to achieve automated discovery of competitor relationships on the basis of structure of an intercompany network derived from company citations (cooccurrence) in online news articles. We also estimate to what extent our approach could extend the competitor relationships available from the data sources, Hoover’s and Mergent

The Relationship of Trust and Information Sharing: A Comparative Study of Suppliers in the US and China

Trust is essential for a business relationship within a supply chain. On the basis of 208 responses from suppliers in the U.S. and China this study empirically tests the relationship between trust and each of five types of manufacture-supplier information sharing. High trust can lead to frequent information sharing between suppliers and manufacturers, such as in new product development, manufacturing process, logistics, and quality control. High trust also cause frequent financial information sharing between buyers and suppliers for Chinese and Japanese brand supply chains while it is not supported for western brand supply chains after in-depth comparative study of four groups suppliers in the U.S. and China

Studies of α-Helicity and Intersegmental Interactions in Voltage-Gated Na+ Channels: S2D4

Much data, including crystallographic, support structural models of sodium and potassium channels consisting of S1–S4 transmembrane segments (the “voltage-sensing domain”) clustered around a central pore-forming region (S5–S6 segments and the intervening loop). Voltage gated sodium channels have four non-identical domains which differentiates them from the homotetrameric potassium channels that form the basis for current structural models. Since potassium and sodium channels also exhibit many different functional characteristics and the fourth domain (D4) of sodium channels differs in function from other domains (D1–D3), we have explored its structure in order to determine whether segments in D4 of sodium channels differ significantly from that determined for potassium channels. We have probed the secondary and tertiary structure and the role of the individual amino acid residues of the S2D4) of Nav1.4 by employing cysteine-scanning mutagenesis (with tryptophan and glutamine substituted for native cysteine). A Fourier transform power spectrum of perturbations in free energy of steady-state inactivation gating (using midpoint potentials and slopes of Boltzmann equation fits of channel availability, h∞-V plots) indicates a substantial amount of α-helical structure in S2D4 (peak at 106°, α-Periodicity Index (α-PI) of 3.10), This conclusion is supported by α-PI values of 3.28 and 2.84 for the perturbations in rate constants of entry into (β) and exit from (α) fast inactivation at 0 mV for mutant channels relative to WT channels assuming a simple two-state model for transition from the open to inactivated state. The results of cysteine substitution at the two most sensitive sites of the S2D4 α-helix (N1382 and E1392C) support the existence of electrostatic network interactions between S2 and other transmembrane segments within Nav1.4D4 similar to but not identical to those proposed for K+ channels

Can Visible Cues of Search Results Tell Vendors\u27 Reliability?

A search engine provides two distinct types of results, organic and paid, each of which uses different mechanisms for selecting and ranking relevant Web pages for a query. For an e-commerce query, vendors represented by websites in these organic and paid results are expected to have varying reliability ratings, such as a satisfactory or unsatisfactory score from the Business Bureau (BBB) based on overall customer experiences. In this paper we empirically examine how vendors’ reliability ratings in BBB are associated with cues (such as type of result, relative price, number of sites selling the product) that can be observed or derived from search results, and further we attempt to predict vendors’ BBB reliability ratings using those cues

An Extracellular Cu2+ Binding Site in the Voltage Sensor of BK and Shaker Potassium Channels

Copper is an essential trace element that may serve as a signaling molecule in the nervous system. Here we show that extracellular Cu2+ is a potent inhibitor of BK and Shaker K+ channels. At low micromolar concentrations, Cu2+ rapidly and reversibly reduces macrosocopic K+ conductance (GK) evoked from mSlo1 BK channels by membrane depolarization. GK is reduced in a dose-dependent manner with an IC50 and Hill coefficient of ∼2 μM and 1.0, respectively. Saturating 100 μM Cu2+ shifts the GK-V relation by +74 mV and reduces GKmax by 27% without affecting single channel conductance. However, 100 μM Cu2+ fails to inhibit GK when applied during membrane depolarization, suggesting that Cu2+ interacts poorly with the activated channel. Of other transition metal ions tested, only Zn2+ and Cd2+ had significant effects at 100 μM with IC50s > 0.5 mM, suggesting the binding site is Cu2+ selective. Mutation of external Cys or His residues did not alter Cu2+ sensitivity. However, four putative Cu2+-coordinating residues were identified (D133, Q151, D153, and R207) in transmembrane segments S1, S2, and S4 of the mSlo1 voltage sensor, based on the ability of substitutions at these positions to alter Cu2+ and/or Cd2+ sensitivity. Consistent with the presence of acidic residues in the binding site, Cu2+ sensitivity was reduced at low extracellular pH. The three charged positions in S1, S2, and S4 are highly conserved among voltage-gated channels and could play a general role in metal sensitivity. We demonstrate that Shaker, like mSlo1, is much more sensitive to Cu2+ than Zn2+ and that sensitivity to these metals is altered by mutating the conserved positions in S1 or S4 or reducing pH. Our results suggest that the voltage sensor forms a state- and pH-dependent, metal-selective binding pocket that may be occupied by Cu2+ at physiologically relevant concentrations to inhibit activation of BK and other channels

Information Sharing with Suppliers to Improve Mass Customization Capability: A Trust Perspective

Trust is essential for business relationships within a supply chain. On the basis of over 200 responses from suppliers in the U.S. and China, this study empirically tests the relationship between trust and manufacturer-supplier information sharing. High trust can lead to frequent information sharing between suppliers and manufacturers. Frequent information sharing causes high mass customization capabilities. The moderating effect of country culture is also found for the relationship between trust and financial information sharing