DPP6 Localization in Brain Supports Function as a Kv4 Channel Associated Protein

The gene encoding the dipeptidyl peptidase-like protein DPP6 (also known as DPPX) has been associated with human neural disease. However, until recently no function had been found for this protein. It has been proposed that DPP6 is an auxiliary subunit of neuronal Kv4 K+ channels, the ion channels responsible for the somato-dendritic A-type K+ current, an ionic current with crucial roles in the regulation of firing frequency, dendritic integration and synaptic plasticity. This view has been supported mainly by studies showing that DPP6 is necessary to generate channels with biophysical properties resembling the native channels in some neurons. However, independent evidence that DPP6 is a component of neuronal Kv4 channels in the brain, and whether this protein has other functions in the CNS is still lacking. We generated antibodies to DPP6 proteins to compare their distribution in brain with that of the Kv4 pore-forming subunits. DPP6 proteins were prominently expressed in neuronal populations expressing Kv4.2 proteins and both types of protein were enriched in the dendrites of these cells, strongly supporting the hypothesis that DPP6 is an associated protein of Kv4 channels in brain neurons. The observed similarity in the cellular and subcellular patterns of expression of both proteins suggests that this is the main function of DPP6 in brain. However, we also found that DPP6 antibodies intensely labeled the hippocampal mossy fiber axons, which lack Kv4 proteins, suggesting that DPP6 proteins may have additional, Kv4-unrelated functions

Mandatory Employment Arbitration: Dispelling the Myths

[Excerpt] Using mandatory arbitration to resolve employment disputes has been a major source of controversy since the practice emerged about twenty‐five years ago. On one side of the debate have been proponents of the practice, who contend that mandatory pre‐dispute arbitration provides a faster and cheaper means of resolving employment disputes than relying on conventional litigation

Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels.

A-type voltage-gated K(+) (Kv) channels self-regulate their activity by inactivating directly from the open state (open-state inactivation [OSI]) or by inactivating before they open (closed-state inactivation [CSI]). To determine the inactivation pathways, it is often necessary to apply several pulse protocols, pore blockers, single-channel recording, and kinetic modeling. However, intrinsic hurdles may preclude the standardized application of these methods. Here, we implemented a simple method inspired by earlier studies of Na(+) channels to analyze macroscopic inactivation and conclusively deduce the pathways of inactivation of recombinant and native A-type Kv channels. We investigated two distinct A-type Kv channels expressed heterologously (Kv3.4 and Kv4.2 with accessory subunits) and their native counterparts in dorsal root ganglion and cerebellar granule neurons. This approach applies two conventional pulse protocols to examine inactivation induced by (a) a simple step (single-pulse inactivation) and (b) a conditioning step (double-pulse inactivation). Consistent with OSI, the rate of Kv3.4 inactivation (i.e., the negative first derivative of double-pulse inactivation) precisely superimposes on the profile of the Kv3.4 current evoked by a single pulse because the channels must open to inactivate. In contrast, the rate of Kv4.2 inactivation is asynchronous, already changing at earlier times relative to the profile of the Kv4.2 current evoked by a single pulse. Thus, Kv4.2 inactivation occurs uncoupled from channel opening, indicating CSI. Furthermore, the inactivation time constant versus voltage relation of Kv3.4 decreases monotonically with depolarization and levels off, whereas that of Kv4.2 exhibits a J-shape profile. We also manipulated the inactivation phenotype by changing the subunit composition and show how CSI and CSI combined with OSI might affect spiking properties in a full computational model of the hippocampal CA1 neuron. This work unambiguously elucidates contrasting inactivation pathways in neuronal A-type Kv channels and demonstrates how distinct pathways might impact neurophysiological activity

Incorporation of DPP6a and DPP6K Variants in Ternary Kv4 Channel Complex Reconstitutes Properties of A-type K Current in Rat Cerebellar Granule Cells

Dipeptidyl peptidase-like protein 6 (DPP6) proteins co-assemble with Kv4 channel α-subunits and Kv channel-interacting proteins (KChIPs) to form channel protein complexes underlying neuronal somatodendritic A-type potassium current (ISA). DPP6 proteins are expressed as N-terminal variants (DPP6a, DPP6K, DPP6S, DPP6L) that result from alternative mRNA initiation and exhibit overlapping expression patterns. Here, we study the role DPP6 variants play in shaping the functional properties of ISA found in cerebellar granule (CG) cells using quantitative RT-PCR and voltage-clamp recordings of whole-cell currents from reconstituted channel complexes and native ISA channels. Differential expression of DPP6 variants was detected in rat CG cells, with DPP6K (41±3%)>DPP6a (33±3%)>>DPP6S (18±2%)>DPP6L (8±3%). To better understand how DPP6 variants shape native neuronal ISA, we focused on studying interactions between the two dominant variants, DPP6K and DPP6a. Although previous studies did not identify unique functional effects of DPP6K, we find that the unique N-terminus of DPP6K modulates the effects of KChIP proteins, slowing recovery and producing a negative shift in the steady-state inactivation curve. By contrast, DPP6a uses its distinct N-terminus to directly confer rapid N-type inactivation independently of KChIP3a. When DPP6a and DPP6K are co-expressed in ratios similar to those found in CG cells, their distinct effects compete in modulating channel function. The more rapid inactivation from DPP6a dominates during strong depolarization; however, DPP6K produces a negative shift in the steady-state inactivation curve and introduces a slow phase of recovery from inactivation. A direct comparison to the native CG cell ISA shows that these mixed effects are present in the native channels. Our results support the hypothesis that the precise expression and co-assembly of different auxiliary subunit variants are important factors in shaping the ISA functional properties in specific neuronal populations

The twilight of the Liberal Social Contract? On the Reception of Rawlsian Political Liberalism

This chapter discusses the Rawlsian project of public reason, or public justification-based 'political' liberalism, and its reception. After a brief philosophical rather than philological reconstruction of the project, the chapter revolves around a distinction between idealist and realist responses to it. Focusing on political liberalism’s critical reception illuminates an overarching question: was Rawls’s revival of a contractualist approach to liberal legitimacy a fruitful move for liberalism and/or the social contract tradition? The last section contains a largely negative answer to that question. Nonetheless the chapter's conclusion shows that the research programme of political liberalism provided and continues to provide illuminating insights into the limitations of liberal contractualism, especially under conditions of persistent and radical diversity. The programme is, however, less receptive to challenges to do with the relative decline of the power of modern states

Constitutivism

A brief explanation and overview of constitutivism

Philosophy of action

The philosophical study of human action begins with Plato and Aristotle. Their influence in late antiquity and the Middle Ages yielded sophisticated theories of action and motivation, notably in the works of Augustine and Aquinas.1 But the ideas that were dominant in 1945 have their roots in the early modern period, when advances in physics and mathematics reshaped philosophy

Does Alternative Dispute Resolution Influence Litigation Filings? An Empirical Assessment Of The Liitgation Profiles Of Fortune 1000 Firms

From the beginning of the "silent ADR revolution" in the 1970s, conflict management scholars have implied that ADR has the capacity to resolve workplace conflicts short of litigation. Yet the Gilmer decision gave firms two strategies for managing workplace disputes: (1) use arbitration to limit the costs associated with litigating workplace claims, or (2) use "conflict management systems" to control the escalation of these claims within the workplace. While many firms employ both strategies, they are rooted in different philosophies of workplace conflicts resolution. The first strategy focuses on "distributive" ADR and is indifferent to repairing the employment relationship. The second method focuses on so-called "win-win" ADR techniques that attempt to find solutions to workplace conflicts that benefit both employers and employees. This thesis provides cross-industry empirical data comparing if both of these strategies are able to influence the number of FLSA and employment discrimination claims filed against Fortune 1000 firms