A-Type KV Channels in Dorsal Root Ganglion Neurons: Diversity, Function, and Dysfunction

A-type voltage-gated potassium (Kv) channels are major regulators of neuronal excitability that have been mainly characterized in the central nervous system. By contrast, there is a paucity of knowledge about the molecular physiology of these Kv channels in the peripheral nervous system, including highly specialized and heterogenous dorsal root ganglion (DRG) neurons. Although all A-type Kv channels display pore-forming subunits with similar structural properties and fast inactivation, their voltage-, and time-dependent properties and modulation are significantly different. These differences ultimately determine distinct physiological roles of diverse A-type Kv channels, and how their dysfunction might contribute to neurological disorders. The importance of A-type Kv channels in DRG neurons is highlighted by recent studies that have linked their dysfunction to persistent pain sensitization. Here, we review the molecular neurophysiology of A-type Kv channels with an emphasis on those that have been identified and investigated in DRG nociceptors (Kv1.4, Kv3.4, and Kv4s). Also, we discuss evidence implicating these Kv channels in neuropathic pain resulting from injury, and present a perspective of outstanding challenges that must be tackled in order to discover novel treatments for intractable pain disorders

Coupling of Smoothened to inhibitory G proteins reduces voltage-gated K

SMO (Smoothened), the central transducer of Hedgehog signaling, is coupled to heterotrimeric Gi proteins in many cell types, including cardiomyocytes. In this study, we report that activation of SMO with SHH (Sonic Hedgehog) or a small agonist, purmorphamine, rapidly causes a prolongation of the action potential duration that is sensitive to a SMO inhibitor. In contrast, neither of the SMO agonists prolonged the action potential in cardiomyocytes from transgenic GiCT/TTA mice, in which Gi signaling is impaired, suggesting that the effect of SMO is mediated by Gi proteins. Investigation of the mechanism underlying the change in action potential kinetics revealed that activation of SMO selectively reduces outward voltage-gated K+ repolarizing (Kv) currents in isolated cardiomyocytes and that it induces a down-regulation of membrane levels of Kv4.3 in cardiomyocytes and intact hearts from WT but not from GiCT/TTA mice. Moreover, perfusion of intact hearts with Shh or purmorphamine increased the ventricular repolarization time (QT interval) and induced ventricular arrhythmias. Our data constitute the first report that acute, noncanonical Hh signaling mediated by Gi proteins regulates K+ currents density in cardiomyocytes and sensitizes the heart to the development of ventricular arrhythmias. © 2018 Cheng et al

Another challenge for scientists

By nature, scientists contribute to our understanding of nature and ourselves. As communities undergo significant changes, new challenges are presented. Here, we offer alternative views on recent changes in society

The problem of choice

Convictions are a driving force for actions. Considering that every individual has a different set of convictions and larger groups act once a consensus decision is reached, one can see that debate is an inherent exercise in decision-making. This requires a sustainably generated surplus to allow time for intellectual exchange, gathering of information and dissemination of findings. It is essential that the full spectrum of options remain treated equally. At the end of this process, a choice has to be made. Looking back at a later time point, a retrospective analysis sometimes reveals that the choice was neither completely free nor a truly conscious one. Leaving the issue of consequences of a once made decision aside, we wish to contribute to the debate of the problem of choice

To know or not to know: archiving and the under-appreciated historical value of data

Surplus goods, produced by a community, allow individuals to dedicate their efforts to abstract problems, while enjoying the benefits of support from the community. In return, the community benefits from the intellectual work, say, efficiently producing goods or profound medical aid. In further elevating quality of life, we need to understand nature and biology on the most detailed level. Inevitably, research costs are increasing along with the need for more scientists to specialize their efforts. As a result, a vast amount of data and information is generated that needs to be archived and made openly accessible with the permission to re-use and re-distribute. With economies undergoing crises and prosperity in an almost cyclic manner, it seems that funding for science and technology follows a similar pattern. Another aspect to the problem of the loss of data is the human propensity, at the level of each individual researcher, to passively discard data in the course of daily life and through a career. In a typical laboratory, significant amounts of information is still stored on disks in file cabinets or on isolated computers, and is lost when a research group disbands. Being conscientious to one's data, to see that it reaches a place in which it can persist beyond the lifespan of any one individual requires responsibility on the part of its creator

Function of reactive oxygen species during animal development: Passive or active?

AbstractOxidative stress is considered causal of aging and pathological cell death, however, very little is known about its function in the natural processes that support the formation of an organism. It is generally thought that cells must continuously protect themselves from the possible damage caused by reactive oxygen species (ROS) (passive ROS function). However, presently, ROS are recognized as physiologically relevant molecules that mediate cell responses to a variety of stimuli, and the activities of several molecules, some developmentally relevant, are directly or indirectly regulated by oxidative stress (active ROS function). Here we review recent data that are suggestive of specific ROS functions during development of animals, particularly mammals

HIPERCONECTIVIDAD Y DESARROLLO DE COMPETENCIAS DIGITALES EN LOS ESTUDIOS DE POSGRADO

El artículo ofrece una revisión al concepto hiperconectividad a partir del desarrollo de competencias digitales en estudiantes y egresados de la Maestría en Gestión y Desarrollo Social de la Universidad de Guadalajara, en el marco de las estrategias propuestas por la Conferencia Mundial sobre la Educación Superior. Se desarrolló una discusión en torno a la dialéctica de las Sociedades del Conocimiento en el contexto de las Ciencias Sociales y Humanidades. El trabajo determina cómo influye la facilidad de la conexión permanente a Internet en el desarrollo de nuevas competencias digitales y sociales con las cuales se contribuye al logro de objetivos institucionales como de la ONU, UNESCO y OCDE.   PALABRAS CLAVE: Competencias digitales, Hiperconectividad, Conectivismo, Inteligencia colectiva, Aprendizaje invisible.     RESUMO O conceito de hiperconectividade faz parte central desse artiago perante o desnvolvimento de competências digitais em estudantes e graduados do Mestrado em Gestão e Desenvolvimento Social da Universidade de Guadalajara, no âmbito das estratégias propostas pela Conferência Mundial de Educação Superior. Uma outra discussão foi desenvolvida em torno da dialética das Sociedades do Conhecimento no contexto das Ciências Sociais e Humanas. O trabalho ou mostra como a facilidade da conexão permanente com a Internet influência o desenvolvimento de novas competências digitais e sociais com as quais contribui para o alcance de objetivos institucionais como a ONU, a UNESCO e a OCDE.   PALAVRAS-CHAVE: Habilidades digitais, hiperconectividade, conectividade, inteligência coletiva, aprendizado invisível.     ABSTRACT This paper offers a review of the concept hyperconnectivity in order to analyze the implementation of digital competences in students and graduates of the Master in Management and Social Development in University of Guadalajara, which can be understood as a strategy of the institution to adopt the guideline proposed by the World Conference on Higher Education within this IES has been implemented. In this way we intend to initiate a discussion about the dialectic of the Knowledge Societies in the context of the Social Sciences and Humanities. The aim of the study is to establish the way in which permanent connection influences in the development of new digital and social skills, which contribute to achieve both the goals of the academic program mentioned before and those proposed by international  organizations such as the UN, UNESCO and OCDE.   KEYWORDS: Digital skills, Hyperconnectivity, Conectivism, Collective intelligence, Invisible learning

Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury.

Spinal cord injury (SCI) patients develop chronic pain involving poorly understood central and peripheral mechanisms. Because dysregulation of the voltage-gated Kv3.4 channel has been implicated in the hyperexcitable state of dorsal root ganglion (DRG) neurons following direct injury of sensory nerves, we asked whether such a dysregulation also plays a role in SCI. Kv3.4 channels are expressed in DRG neurons, where they help regulate action potential (AP) repolarization in a manner that depends on the modulation of inactivation by protein kinase C (PKC)-dependent phosphorylation of the channel\u27s inactivation domain. Here, we report that, 2 weeks after cervical hemicontusion SCI, injured rats exhibit contralateral hypersensitivity to stimuli accompanied by accentuated repetitive spiking in putative DRG nociceptors. Also in these neurons at 1 week after laminectomy and SCI, Kv3.4 channel inactivation is impaired compared with naive nonsurgical controls. At 2-6 weeks after laminectomy, however, Kv3.4 channel inactivation returns to naive levels. Conversely, Kv3.4 currents at 2-6 weeks post-SCI are downregulated and remain slow-inactivating. Immunohistochemistry indicated that downregulation mainly resulted from decreased surface expression of the Kv3.4 channel, as whole-DRG-protein and single-cell mRNA transcript levels did not change. Furthermore, consistent with Kv3.4 channel dysregulation, PKC activation failed to shorten the AP duration of small-diameter DRG neurons. Finally, re-expressing synthetic Kv3.4 currents under dynamic clamp conditions dampened repetitive spiking in the neurons from SCI rats. These results suggest a novel peripheral mechanism of post-SCI pain sensitization implicating Kv3.4 channel dysregulation and potential Kv3.4-based therapeutic interventions

The TSC-mTOR pathway regulates macrophage polarization

Macrophages are able to polarize to proinflammatory M1 or alternative M2 states with distinct phenotypes and physiological functions. How metabolic status regulates macrophage polarization remains not well understood, and here we examine the role of mTOR (Mechanistic Target of Rapamycin), a central metabolic pathway that couples nutrient sensing to regulation of metabolic processes. Using a mouse model in which myeloid lineage specific deletion of Tsc1 (Tsc1Δ/Δ) leads to constitutive mTOR Complex 1 (mTORC1) activation, we find that Tsc1Δ/Δ macrophages are refractory to IL-4 induced M2 polarization, but produce increased inflammatory responses to proinflammatory stimuli. Moreover, mTORC1-mediated downregulation of Akt signaling critically contributes to defective polarization. These findings highlight a key role for the mTOR pathway in regulating macrophage polarization, and suggest how nutrient sensing and metabolic status could be “hard-wired” to control of macrophage function, with broad implications for regulation of Type 2 immunity, inflammation, and allergy