Does PtdIns(4,5)P2 concentrate so it can multi-task?

2016 ◽  
Vol 44 (1) ◽  
pp. 228-233 ◽  
Author(s):  
Gerald R.V. Hammond
Keyword(s):  
Protein Complexes ◽  
Second Messengers ◽  
Open Questions ◽  
Signalling Molecule ◽  
Health And Disease ◽  
Bona Fide ◽  
Experimental Approaches ◽  
Structural Lipid ◽  
A Minor ◽  
Protein Recruitment

Ptdns(4,5)P2 is a minor structural lipid of the plasma membrane (PM), but a master regulator of PM function. Serving either as a substrate for the generation of second messengers, or more commonly as a ligand triggering protein recruitment or activation, it regulates most aspects of PM function. Understanding how this relatively simple biological macromolecule can regulate such a vast array of different functions in parallel, is the key to understanding the biology of the PM as a whole, in both health and disease. In this review, potential mechanisms are discussed that might explain how a lipid can separately regulate so many protein complexes. The focus is on the spatial distribution of the lipid molecules, their metabolism and their interactions. Open questions that still need to be resolved are highlighted, as are potential experimental approaches that might shed light on the mechanisms at play. Moreover, the broader question is raised as to whether PtdIns(4,5)P2 should be thought of as a bona fide signalling molecule or more of a simple lipid cofactor or perhaps both, depending on the context of the particular function in question.

Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

2020 ◽  
Vol 13 (663) ◽  
pp. eabd8379
Author(s):  
Heba Ali ◽  
Lena Marth ◽  
Dilja Krueger-Burg
Keyword(s):  
Synaptic Transmission ◽  
Synapse Formation ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inhibitory Synapses ◽  
Molecular Architecture ◽  
Cellular Functions ◽  
Altered Expression ◽  
Health And Disease ◽  
Flow Of Information

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

scholarly journals Reactive Oxygen Species: Beyond Their Reactive Behavior

2021 ◽  
Vol 46 (1) ◽  
pp. 77-87
Author(s):  
Arnaud Tauffenberger ◽  
Pierre J. Magistretti
Keyword(s):  
Reactive Oxygen Species ◽  
Second Messengers ◽  
Critical Role ◽  
Complex Function ◽  
Reactive Oxygen ◽  
High Reactivity ◽  
Oxygen Species ◽  
Health And Disease ◽  
Cellular Dysfunction ◽  
The Brain

AbstractCellular homeostasis plays a critical role in how an organism will develop and age. Disruption of this fragile equilibrium is often associated with health degradation and ultimately, death. Reactive oxygen species (ROS) have been closely associated with health decline and neurological disorders, such as Alzheimer’s disease or Parkinson’s disease. ROS were first identified as by-products of the cellular activity, mainly mitochondrial respiration, and their high reactivity is linked to a disruption of macromolecules such as proteins, lipids and DNA. More recent research suggests more complex function of ROS, reaching far beyond the cellular dysfunction. ROS are active actors in most of the signaling cascades involved in cell development, proliferation and survival, constituting important second messengers. In the brain, their impact on neurons and astrocytes has been associated with synaptic plasticity and neuron survival. This review provides an overview of ROS function in cell signaling in the context of aging and degeneration in the brain and guarding the fragile balance between health and disease.

scholarly journals Physiology of guanosine-based second messenger signaling in Bacillus subtilis

2020 ◽  
Vol 401 (12) ◽  
pp. 1307-1322
Author(s):  
Gert Bange ◽  
Patricia Bedrunka
Keyword(s):  
Bacillus Subtilis ◽  
Biofilm Formation ◽  
Second Messengers ◽  
Model Organism ◽  
Physiological Regulation ◽  
Open Questions ◽  
Key Players ◽  
Stress Signals ◽  
Second Messenger Signaling ◽  
Synthesis And Degradation

AbstractThe guanosine-based second messengers (p)ppGpp and c-di-GMP are key players of the physiological regulation of the Gram-positive model organism Bacillus subtilis. Their regulatory spectrum ranges from key metabolic processes over motility to biofilm formation. Here we review our mechanistic knowledge on their synthesis and degradation in response to environmental and stress signals as well as what is known on their cellular effectors and targets. Moreover, we discuss open questions and our gaps in knowledge on these two important second messengers.

scholarly journals An AP-3-dependent mechanism drives synaptic-like microvesicle biogenesis in pancreatic islet β-cells

2010 ◽  
Vol 299 (1) ◽  
pp. E23-E32 ◽  
Author(s):  
Arthur T. Suckow ◽  
Branch Craige ◽  
Victor Faundez ◽  
William J. Cain ◽  
Steven D. Chessler
Keyword(s):  
Synaptic Vesicle ◽  
Pancreatic Islet ◽  
Membrane Trafficking ◽  
Protein Complexes ◽  
Brefeldin A ◽  
Adaptor Protein ◽  
Β Cells ◽  
Β Cell ◽  
Subunit Expression ◽  
Bona Fide

Pancreatic islet β-cells contain synaptic-like microvesicles (SLMVs). The origin, trafficking, and role of these SLMVs are poorly understood. In neurons, synaptic vesicle (SV) biogenesis is mediated by two different cytosolic adaptor protein complexes, a ubiquitous AP-2 complex and the neuron-specific AP-3B complex. Mice lacking AP-3B subunits exhibit impaired GABAergic (inhibitory) neurotransmission and reduced neuronal vesicular GABA transporter (VGAT) content. Since β-cell maturation and exocytotic function seem to parallel that of the inhibitory synapse, we predicted that AP-3B-associated vesicles would be present in β-cells. Here, we test the hypothesis that AP-3B is expressed in islets and mediates β-cell SLMV biogenesis. A secondary aim was to test whether the sedimentation properties of INS-1 β-cell microvesicles are identical to those of bona fide SLMVs isolated from PC12 cells. Our results show that the two neuron-specific AP-3 subunits β3B and μ3B are expressed in β-cells, the first time these proteins have been found to be expressed outside the nervous system. We found that β-cell SLMVs share the same sedimentation properties as PC12 SLMVs and contain SV proteins that sort specifically to AP-3B-associated vesicles in the brain. Brefeldin A, a drug that interferes with AP-3-mediated SV biogenesis, inhibits the delivery of AP-3 cargoes to β-cell SLMVs. Consistent with a role for AP-3 in the biogenesis of GABAergic SLMV in β-cells, INS-1 cell VGAT content decreases upon inhibition of AP-3 δ-subunit expression. Our findings suggest that β-cells and neurons share molecules and mechanisms important for mediating the neuron-specific membrane trafficking pathways that underlie synaptic vesicle formation.

scholarly journals Emerging mass spectrometry-based proteomics methodologies for novel biomedical applications

2020 ◽  
Vol 48 (5) ◽  
pp. 1953-1966
Author(s):  
Lindsay K. Pino ◽  
Jacob Rose ◽  
Amy O'Broin ◽  
Samah Shah ◽  
Birgit Schilling
Keyword(s):  
Mass Spectrometry ◽  
Human Health ◽  
Protein Complexes ◽  
Protein Quantification ◽  
Intact Protein ◽  
Protein Signaling ◽  
Post Translational Modifications ◽  
Protein Protein Interaction ◽  
Health And Disease ◽  
Proteomics Research

Research into the basic biology of human health and disease, as well as translational human research and clinical applications, all benefit from the growing accessibility and versatility of mass spectrometry (MS)-based proteomics. Although once limited in throughput and sensitivity, proteomic studies have quickly grown in scope and scale over the last decade due to significant advances in instrumentation, computational approaches, and bio-sample preparation. Here, we review these latest developments in MS and highlight how these techniques are used to study the mechanisms, diagnosis, and treatment of human diseases. We first describe recent groundbreaking technological advancements for MS-based proteomics, including novel data acquisition techniques and protein quantification approaches. Next, we describe innovations that enable the unprecedented depth of coverage in protein signaling and spatiotemporal protein distributions, including studies of post-translational modifications, protein turnover, and single-cell proteomics. Finally, we explore new workflows to investigate protein complexes and structures, and we present new approaches for protein–protein interaction studies and intact protein or top-down MS. While these approaches are only recently incipient, we anticipate that their use in biomedical MS proteomics research will offer actionable discoveries for the improvement of human health.

scholarly journals Hydrogen sulfide: stench from the past as a mediator of the future

2016 ◽  
Vol 38 (5) ◽  
pp. 12-17 ◽  
Author(s):  
Jasmina Zivanovic ◽  
Milos R. Filipovic
Keyword(s):  
Blood Pressure ◽  
Hydrogen Sulfide ◽  
Human Body ◽  
The Past ◽  
Ability To Act ◽  
Signalling Molecule ◽  
Actual Mechanism ◽  
Growing Body ◽  
Health And Disease ◽  
Pharmacological Potential

The past decade has witnessed the discovery of hydrogen sulfide (H2S) as a new signalling molecule. Its ability to act as a neurotransmitter, regulator of blood pressure, immunomodulator or anti-apoptotic agent, together with its great pharmacological potential, is now well established. Notwithstanding the growing body of evidence showing the biological roles of H2S, the gap between these roles and the actual mechanism(s) behind these processes is getting larger. We propose a way that protein cysteine residues can be modified to form protein persulfides (P-SSH) and explain how this process is controlled in a physiologically relevant fashion. This article provides an overview of H2S signalling in the human body with particular emphasis on the latest discoveries regarding the mechanisms of protein persulfidation and depersulfidation, as well as about the biological reactivity of persulfides and their role in health and disease.

scholarly journals State Capacity Redux: Integrating Classical and Experimental Contributions to an Enduring Debate

2018 ◽  
Vol 21 (1) ◽  
pp. 71-91 ◽  
Author(s):  
Elissa Berwick ◽  
Fotini Christia
Keyword(s):  
State Capacity ◽  
Empirical Work ◽  
The State ◽  
Interactive Process ◽  
Theoretical Structure ◽  
State Activity ◽  
Open Questions ◽  
Mass Publics ◽  
Experimental Approaches ◽  
The Subject

What state capacity is and how to strengthen it remain open questions, as the underlying incentives of the state, its citizens, and its agents align in some areas of state activity and diverge in others. This article lays out a framework that integrates classical and experimental approaches within a common theoretical structure based on the diverse capacity challenges states face with respect to extraction, coordination, and compliance. Addressing each in turn, we show that state capacity is an interactive process, the product of institutions governing relations between the state, mass publics, and bureaucrats. We argue that the institutions ensuring capacity and the processes that bring them into being vary. Our review highlights trends in recent research, as well as relevant differences in opportunities for and obstacles to empirical work on the subject.

scholarly journals A Computational Perspective of the Role of the Thalamus in Cognition

2019 ◽  
Vol 31 (7) ◽  
pp. 1380-1418 ◽  
Author(s):  
Nima Dehghani ◽  
Ralf D. Wimmer
Keyword(s):  
Cognitive Capacity ◽  
Contextual Modulation ◽  
Dynamic Selection ◽  
Thalamic Relay ◽  
Health And Disease ◽  
Experimental Approaches ◽  
Cortical Inputs ◽  
Reasonable Description ◽  
Cortical Representations

The thalamus has traditionally been considered as only a relay source of cortical inputs, with hierarchically organized cortical circuits serially transforming thalamic signals to cognitively relevant representations. Given the absence of local excitatory connections within the thalamus, the notion of thalamic relay seemed like a reasonable description over the past several decades. Recent advances in experimental approaches and theory provide a broader perspective on the role of the thalamus in cognitively relevant cortical computations and suggest that only a subset of thalamic circuit motifs fits the relay description. Here, we discuss this perspective and highlight the potential role for the thalamus, and specifically the mediodorsal (MD) nucleus, in the dynamic selection of cortical representations through a combination of intrinsic thalamic computations and output signals that change cortical network functional parameters. We suggest that through the contextual modulation of cortical computation, the thalamus and cortex jointly optimize the information and cost trade-off in an emergent fashion. We emphasize that coordinated experimental and theoretical efforts will provide a path to understanding the role of the thalamus in cognition, along with an understanding to augment cognitive capacity in health and disease.

scholarly journals MiR-146a/b: a family with shared seeds and different roots

2017 ◽  
Vol 49 (4) ◽  
pp. 243-252 ◽  
Author(s):  
Mark R. Paterson ◽  
Alison J. Kriegel
Keyword(s):  
Target Genes ◽  
Family Members ◽  
Differential Regulation ◽  
Seed Region ◽  
Small Noncoding Rnas ◽  
Specific Effects ◽  
Exciting Potential ◽  
Health And Disease ◽  
Experimental Approaches ◽  
Functional Relevance

MicroRNAs are small, noncoding, RNAs known for their powerful modulation of molecular processes, making them a major focus for studying pathological mechanisms. The human miR-146 family of microRNAs consists of two member genes, MIR146A and MIR146B. These two microRNAs are located on different chromosomes and exhibit differential regulation in many cases. However, they are nearly identical in sequence, sharing a seed region, and are thus predicted to target the same set of genes. A large proportion of the microRNA (miR)-146 literature focuses on its role in regulating the innate immune response in the context of various pathologies by modulating two widely studied target genes in the toll-like receptor signaling cascade. A growing subset of the literature reports a role of miR-146 in cardiovascular and renal disease, and data suggest there is exciting potential for miR-146 as a diagnostic and therapeutic target. Nevertheless, the published literature is confounded by unclear and imprecise language concerning the specific effects of the two miR-146 family members. The present review will compare the genomic origin and regulation of miR-146a and miR-146b, discuss some approaches to overcome analytical and experimental challenges, and summarize findings in major areas of miR-146 research. Moving forward, careful evaluation of miR-146a/b specificity in analytical and experimental approaches will aid researchers in elucidating the functional relevance of differential regulation of the miR-146 family members in health and disease.

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