1,721,043 research outputs found
From cell protection to death: may Ca2+ signals explain the chameleonic attributes of the mammalian prion protein?
No full textIt is now accepted that a conformational change of the cellular prion protein (PrP(C)) generates the prion, the infectious agent responsible for lethal neurodegenerative disorders, named transmissible spongiform encephalopathies, or prion diseases. The mechanisms of prion-associated neurodegeneration are still obscure, as is the cell role of PrP(C), although increasing evidence attributes to PrP(C) important functions in cell survival. Such a behavioral dichotomy thus enables the prion protein to switch from a benign role under normal conditions, to the execution of neurons during disease. By reviewing data from models of prion disease and PrP(C)-null paradigms, which suggest a relation between the prion protein and Ca(2+) homeostasis, here we discuss the possibility that Ca(2+) is the factor behind the enigma of the pathophysiology of PrP(C). Ca(2+) features in almost all processes of cell signaling, and may thus tell us much about a protein that pivots between health and disease
Physiopathologic implications of the structural and functional domains of the prion protein
No full textPrion diseases are invariably fatal neurodegenerative disorders affecting man and various animal species. A large body of evidence supports the notion that the causative agent of these diseases is the prion, which, devoid of nucleic acids, is composed largely, if not entirely, of a conformationally abnormal isoform (PrP(Sc) of the cellular prion protein (PrPc). PrPc is a highly conserved and ubiquitously expressed sialoglycoprotein, the normal function of which is, however, still ill defined. Several modules have been recognised in PrPc structure. Their extensive analysis by different experimental approaches, including transgenic animal models, has allowed to assigning to several modules a putative role in PrPc physiology. Concurrently, it has underscored the possibility that alteration of specific domains may determine the switching from a beneficial role of PrPc into one that becomes detrimental to neurons, and/or promote the conversion of PrPc into the pathogenic PrP(Sc) conformer
Is indeed the prion protein an Harlequin servant of "many" masters?
Full text linkTens of putative interacting partners of the cellular prion protein (PrP(C)) have been identified, yet the physiologic role of PrP(C) remains unclear. For the first time, however, a recent paper has demonstrated that the absence of PrP(C) produces a lethal phenotype. Starting from this evidence, here we discuss the validity of past and more recent literature supporting that, as part of protein platforms at the cell surface, PrP(C) may bridge extracellular matrix molecules and/or membrane proteins to intracellular signaling pathways
Accumulation of long-lasting inactivation in rat brain K+-channels
No full textWe studied the phenomenon of cumulative inactivation in the voltage-dependent K+ channels of the Shaker-related subfamily Kv1 cloned from rat brain and expressed in Xenopus oocytes. In Kv1.4, repetitive stimulations at intervals shorter than 20 s produce cumulative inactivation even for brief stimuli that elicit K+ currents which do not show any significant decline during the depolarising pulse. These effects are absent or greatly reduced in the clones Kv1.1, Kv1.3, Kv1.5 and Kv1.6, and in the deletion mutant Kv1.4-delta-110, characterised by lack of "fast" (N-type) inactivation. We find that the inactivation caused by a single pulse increases after the pulse while the channels deactivate, and subsides with two time constants, indicating the existence of (at least) two inactivated states: IS, with a slow recovery kinetics and IF, with faster kinetics. In the simplest kinetic scheme accounting for our observations, IF is coupled sequentially to the open state O, while IS can be reached at a fast rate both from IF and from a pre-open, activated state, A, that is in fast equilibrium with O. The accumulation of long-lasting inactivation during the repolarisation is favoured by the prolongation of the lifetime of activated states due to the presence of IF. This explains the smaller accumulation effect observed in channels lacking fast inactivation. The physiological implications of these findings suggest how different channels of the Kv1 subfamily can affect differently the firing behaviour of neurones
ACTIVATION AND DEACTIVATION PROPERTIES OF RAT-BRAIN K+ CHANNELS OF THE SHAKER-RELATED SUBFAMILY
No full textWe studied the activation properties of members of the Shaker-related subfamily of voltage-gated K+ channels cloned from rat brain and expressed in Xenopus oocytes. We find that Kv1.1, Kv1.4, Kv1.5, and Kv1.6 have similar activation and deactivation kinetics. The k+ currents produced by step depolarisations increase with a sigmoidal time course that can be described by a delay and by the derivative of the current at the inflection point. The delay tends to zero and the logarithmic derivative seems to approach a finite value at large positive voltages, but these asymptotic values are not yet reached at +80 mV. Deactivation of the currents upon stepping to negative membrane potentials below -60 mV is fairly well described by a single exponential. The decrease of the deactivation time constant at increasingly negative voltages tends to become less steep, indicating that this parameter also has a finite limiting value, which is not yet reached, however, at -160 mV. The various clones studied have very similar voltage dependencies of activation with half-activation voltages ranging between -50 and -11 mV and maximum steepness yielding and e-fold change for voltage increments between 3.8 and 7.0 mV. The shallower activation curve of Kv1.4 is likely to be due to coupling with the fast inactivation process present in this clone
Almost a century of prion protein(s): From pathology to physiology, and back to pathology
No full textPrions are one of the few pathogens whose name is renowned at all population levels, after the dramatic
years pervaded by the fear of eating prion-infected food. If now this, somehow irrational, scare of bovine
meat inexorably transmitting devastating brain disorders is largely subdued, several prion-related issues
are still unsolved, precluding the design of therapeutic approaches that could slow, if not halt, prion
diseases.
One unsolved issue is, for example, the role of the prion protein (PrPC), whole conformational misfolding
originates the prion but whose physiologic reason d'etre in neurons, and in cells at large, remains
enigmatic. Preceded by a historical outline, the present review will discuss the functional pleiotropicity
ascribed to PrPC, and whether this aspect could fall, at least in part, into a more concise framework. It will
also be devoted to radically different perspectives for PrPC, which have been recently brought to the
attention of the scientific world with unexpected force. Finally, it will discuss the possible reasons
allowing an evolutionary conserved and benign protein, as PrPC is, to turn into a high affinity receptor for
pathologic misfolded oligomers, and to transmit their toxic message into neurons
Neuronal pathophysiology featuring PrPCand its control over Ca2+metabolism
Full text linkCalcium (Ca2+) is an intracellular second messenger that ubiquitously masters remarkably diverse biological processes, including cell death. Growing evidence substantiates an involvement of the prion protein (PrPC) in regulating neuronal Ca2+homeostasis, which could rationalize most of the wide range of functions ascribed to the protein. We have recently demonstrated that PrPCcontrols extracellular Ca2+fluxes, and mitochondrial Ca2+uptake, in neurons stimulated with glutamate (De Mario et al., J Cell Sci 2017; 130:2736-46), suggesting that PrPCprotects neurons from threatening Ca2+overloads and excitotoxicity. In light of these results and of recent reports in the literature, here we review the connection of PrPCwith Ca2+metabolism and also provide some speculative hints on the physiologic outcomes of this link. In addition, because PrPCis implicated in neurodegenerative diseases, including prion disorders and Alzheimer's disease, we will also discuss possible ways by which disruption of PrPC-Ca2+association could be mechanistically connected with these pathologies
Mitochondrial Channels
No full textEukaryotic cells are living organisms surrounded by a surface membrane, which also house other membranes that define intracellular organelles. Membranes are lipidic structures impermeable to hydrophilic molecules (polar or charged); this is why they harbour proteins, called ion channels and carriers, catalysing the life-requiring exchange of material between a cell and the external space, and between organelles and the cytoplasm. At variance from carriers, ion channels form aqueous pores crossing the lipid bilayer that allow the highly selective transmembrane passage of charged species, namely inorganic ions (e.g. Na+, K+, Ca2+, Cl-), with high potency (105-108 ions per second are transported by a single molecule); they also possess regulatory domains that open and close the pore upon specific stimuli (electric or chemical). Mitochondria are organelles composed of two membranes, in either of which channels are present. However, while channels in the outer membrane (OM) are justified by its the overall high permeability, the finding of these entities in the inner membrane (IM) was unexpected in view of its implication in the process of oxidative phosphorylation that imposes an extremely controlled permeability to ions. After the initial phenomenological description, substantial advances in the functional - if not molecular - identification of several mitochondrial channels, disclose the possibility that they take part in crucial schemes of mitochondrial functionality, as well as in dramatic cell events
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