440 research outputs found
Modal gating of human Ca(v)2.1 (P/Q-type) calcium channels: II. The b mode and reversible uncoupling of inactivation
No full texthe single channel gating properties of human Ca(V)2.1 (P/Q-type) calcium channels were investigated with cell-attached patch-clamp recordings on HEK293 cells stably expressing these calcium channels. Human Ca(V)2.1 channels showed a complex modal gating, which is described in this and the preceding paper (Luvisetto, S., T. Fellin, M. Spagnolo, B. Hivert, RE Brust, M.M. Harpold, K.A. Stauderman, M.E. Williams, and D. Pietrobon. 2004. J Gev. Physiol. 124:445-461). Here, we report the characterization of the so-called b gating mode. A Ca(V)2.1 channel in the b gating mode shows a bell-shaped voltage dependence of the open probability and a characteristic low open probability at high positive voltages, that decreases with increasing voltage, as a consequence of both shorter mean open time and longer mean closed time. Reversible transitions of single human Ca(V)2.1 channels between the b gating mode and the mode of gating in which the channel shows the usual voltage dependence of the open probability (nb gating mode) were much more frequent (time scale of seconds) than those between the slow and fast gating modes (time scale of minutes; Luvisetto et al., 2004), and Occurred independently of whether the channel was in the fast or slow mode. We show that the b gating mode produces reversible uncoupling of inactivation in human Ca(V)2.1 channels. In fact, a Ca(V)2.1 channel in the b gating mode does not inactivate during long pulses at high positive voltages, where the same channel in both fast-nb and slow-jib gating modes inactivates relatively rapidly Moreover, a Ca(V)2.1 channel in the b gating mode shows a larger availability to open than in the rib gating modes. Regulation of the complex modal gating of human Ca(V)2.1 channels could be a potent and verb satile mechanism for the modulation of synaptic strength and plasticity as well as of neuronal excitability and other postsynaptic Ca2+-dependent processes
La serie storica di Udine: analisi dell'evoluzione delle temperature e delle precipitazioni negli ultimi cento anni
No full textLa Previsione delle Precipitazioni a scala mensile - confronto tra modelli statistici e a reti neurali: il caso di Udine
No full textPrevisioni a scala mensile delle precipitazioni della città di Udine: confronto tra modelli stocastici di tipo TARSO e modelli a reti neurali
No full textFunction and dysfunction of synaptic calcium channels: insights from mouse models
No full textIn the past few years several spontaneous or engineered mouse models with mutations in Ca2+ channel genes have become available, providing a powerful approach to defining Ca2+ channel function in vivo. There have been recent advances in outlining the phenotypes and in the functional analysis of mouse models with mutations in genes encoding the pore-forming subunits of Ca(V)2.1 (P/Q-type), Ca(V)2.2 (N-type) and Ca(V)2.3 (R-type) Ca2+ channels, the channels involved in controlling neurotransmitter release at mammalian synapses. These data indicate that Ca(V)2.1 channels have a dominant and efficient specific role in initiating fast synaptic transmission at central excitatory synapses in vivo, and suggest that the Ca(V)2.1 channelopathies are primarily synaptic diseases. The different disorders probably arise from disruption of neurotransmission in specific brain regions: the cortex in the case of migraine, the thalamus in the case of absence epilepsy and the cerebellum in the case of ataxia
Familial Hemiplegic Migraine
No full textFamilial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCAA 1A, encoding the pore-forming alpha(1) subunits of the neuronal voltage-gated Ca2+ channels Ca(v)2.1 and Na+ channels Na(v)l.l, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the alpha(2) subunit of the Na+, K+ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHMI knockin mice and of several FHM mutants in heterologous expression systems (12 FHMI, 8 FHM2, and I FHM3). These studies show the following: (1) FHMI mutations produce gain-of-function of the Ca(v)2.1 channel and, as a consequence, increased Ca(v)2.1 -dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phe-omenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the zeta(2) Na+,K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(v)1.5 (and presumably Na(v)1. 1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment
Migraine: New molecular mechanisms
No full textMigraine is an episodic headache disorder affecting more than 10% of the general population. Migraine arises from a primary brain dysfunction that leads to activation and sensitization of the trigeminovascular system. A major incompletely understood issue in the neurobiology of migraine concerns the molecular and cellular mechanisms that underlie the primary brain dysfunction and lead to activation and sensitization of the trigeminovascular system, thus generating and maintaining migraine pain. Here the author reviews recent discoveries that have advanced our understanding of these mechanisms toward a unifying pathophysiological hypothesis, in which cortical spreading depression (CSD), the phenomenon underlying migraine aura, assumes a key role. In particular, the author discusses the main recent findings in the genetics and neurobiology of familial hemiplegic migraine and the insights they provide into the molecular and cellular mechanisms that may lead to the increased susceptibility of CSD in migraineurs
CaV2.1 channelopathies
No full textMutations in the CACNA1A gene that encodes the pore-forming alpha(1) subunit of human voltage-gated Ca(V)2.1 (P/Q-type) Ca(2+) channels cause several autosomal-dominant neurologic disorders, including familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). For each channelopathy, the review describes the disease phenotype as well as the functional consequences of the disease-causing mutations on recombinant human Ca(V)2.1 channels and, in the case of FHM1 and SCA6, on neuronal Ca(V)2.1 channels expressed at the endogenous physiological level in knockin mouse models. The effects of FHM1 mutations on cortical spreading depression, the phenomenon underlying migraine aura, and on cortical excitatory and inhibitory synaptic transmission in FHM1 knockin mice are also described, and their implications for the disease mechanism discussed. Moreover, the review describes different ataxic spontaneous cacna1a mouse mutants and the important insights into the cerebellar mechanisms underlying motor dysfunction caused by mutant Ca(V)2.1 channels that were obtained from their functional characterization
Unified Dark Matter models with fast transition
No full textWe investigate the general properties of Unified Dark Matter (UDM) fluid models where the pressure and the energy density are linked by a barotropic equation of state (EoS) p = p(ρ) and the perturbations are adiabatic. The EoS is assumed to admit a future attractor that acts as an effective cosmological constant, while asymptotically in the past the pressure is negligible. UDM models of the dark sector are appealing because they evade the so-called ``coincidence problem'' and ``predict'' what can be interpreted as wDE ≈ −1, but in general suffer the effects of a non-negligible Jeans scale that wreak havoc in the evolution of perturbations, causing a large Integrated Sachs-Wolfe effect and/or changing structure formation at small scales. Typically, observational constraints are violated, unless the parameters of the UDM model are tuned to make it indistinguishable from ΛCDM. Here we show how this problem can be avoided, studying in detail the functional form of the Jeans scale in adiabatic UDM perturbations and introducing a class of models with a fast transition between an early Einstein-de Sitter CDM-like era and a later ΛCDM-like phase. If the transition is fast enough, these models may exhibit satisfactory structure formation and CMB fluctuations. To consider a concrete case, we introduce a toy UDM model and show that it can predict CMB and matter power spectra that are in agreement with observations for a wide range of parameter values
Racconti di case in rovina. Gianni Celati e John Berger, dal letterario al filmico. In: G. BALDASSARRI, V. DI IASIO, G. FERRONI, E. PIETROBON. I cantieri dell’italianistica. Ricerca, didattica e organizzazione agli inizi del XXI secolo. p. 1-6. ROMA: ADI EDITORE. ISBN: 9788846746504
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