Stable, synthetic analogs of diadenosine tetraphosphate inhibit rat and human P2X3 receptors and inflammatory pain.

Background: A growing body of evidence suggests that ATP-gated P2X3 receptors (P2X3Rs) are implicated in chronic pain. We address the possibility that stable, synthetic analogs of diadenosine tetraphosphate (Ap4A) might induce antinociceptive effects by inhibiting P2X3Rs in peripheral sensory neurons.

Results: The effects of two stable, synthetic Ap4A analogs (AppNHppA and AppCH2ppA) are studied firstly in vitro on HEK293 cells expressing recombinant rat P2XRs (P2X2Rs, P2X3Rs, P2X4Rs, and P2X7Rs) and then using native rat brain cells (cultured trigeminal, nodose, or dorsal root ganglion neurons).

Inhibition of Spinal Ca(2+)-Permeable AMPA Receptors with Dicationic Compounds Alleviates Persistent Inflammatory Pain without Adverse Effects.

Upregulation of Ca(2+)-permeable AMPA receptors (CP-AMPARs) in the dorsal horn (DH) neurons of the spinal cord has been causally linked to the maintenance of persistent inflammatory pain. Therefore, inhibition of CP-AMPARs could potentially alleviate an, otherwise, poorly treatable chronic pain. However, a loss of CP-AMPARs could produce considerable side effects because of the crucial role of CP-AMPARs in synaptic plasticity.

HIF-1α-mediated upregulation of SERCA2b: The endogenous mechanism for alleviating the ischemia-induced intracellular Ca(2+) store dysfunction in CA1 and CA3 hippocampal neurons.

Pyramidal neurons of the hippocampus possess differential susceptibility to the ischemia-induced damage with the highest vulnerability of CA1 and the lower sensitivity of CA3 neurons. This damage is triggered by Ca(2+)-dependent excitotoxicity and can result in a delayed cell death that might be potentially suspended through activation of endogenous neuroprotection with the hypoxia-inducible transcription factors (HIF). However, the molecular mechanisms of this neuroprotection remain poorly understood.

Developing electrical properties of postnatal mouse lumbar motoneurons.

We studied the rapid changes in electrical properties of lumbar motoneurons between postnatal days 3 and 9 just before mice weight-bear and walk. The input conductance and rheobase significantly increased up to P8. A negative correlation exists between the input resistance (Rin) and rheobase.

Dynamic excitation states and firing patterns are controlled by sodium channel kinetics in myenteric neurons: a simulation study.

Enteric neurons located in the gastro-intestinal tract are of particular importance to control digestive functions such as motility and secretion. In our recent publication, we showed that mouse myenteric neurons exhibit 2 types of tetrodotoxin-resistant Na(+) currents: a fast inactivating Na(+) current produced by Nav1.5 channels, present in nearly all myenteric neurons, and a persistent Na(+) current attributed to Nav1.

Specialized functions of Nav1.5 and Nav1.9 channels in electrogenesis of myenteric neurons in intact mouse ganglia.

Voltage-gated sodium (Nav) channels play a central role in gastrointestinal physiology because they transmit depolarizing impulses in enteric neurons, thereby enabling the coordination of intestinal motility. However, little is known about the ion channel machinery that specifies firing pattern of enteric neurons. Here, we used in situ patch-clamp recording of myenteric neurons from mice to define functionally the Nav channel subtypes responsible for the electrical signature of myenteric neurons.

Regulation of TRPV1 ion channel by phosphoinositide (4,5)-bisphosphate: the role of membrane asymmetry.

Membrane asymmetry is essential for generating second messengers that act in the cytosol and for trafficking of membrane proteins and membrane lipids, but the role of asymmetry in regulating membrane protein function remains unclear. Here we show that the signaling lipid phosphoinositide 4,5-bisphosphate (PI(4,5)P2) has opposite effects on the function of TRPV1 ion channels depending on which leaflet of the cell membrane it resides in. We observed potentiation of capsaicin-activated TRPV1 currents by PI(4,5)P2 in the intracellular leaflet of the plasma membrane but inhibition of capsaicin-activated currents when PI(4,5)P2 was in both leaflets of the membrane, although much higher concentrations of PI(4,5)P2 in the extracellular leaflet were required for inhibition compared with the concentrations of PI(4,5)P2 in the intracellular leaflet that produced activation.

Spatial heterogeneity of passive electrical transfer properties of neuronal dendrites due to their metrical asymmetry.

The complex and diverse geometry of neuronal dendrites determines the different morphological types of neurons and influences the generation of complex and diverse discharge patterns at the cell output. The recent finding that each temporal pattern has its spatial signature in the form of a combination of high- and low-depolarization states of asymmetrical dendritic branches with active membrane properties raises the question of the nature of such characteristic spatial heterogeneity of electrical states. To answer this, we consider passive dendrites as a conventional reference case using the known current transfer functions, which we complete by corresponding parametric sensitivity functions.

The electro-dynamics of the dendritic space in Purkinje cells of the cerebellum.

The functional geometry of the reconstructed dendritic arborization of Purkinje neurons is the object of this work. The combined effects of the local geometry of the dendritic branches and of the membrane mechanisms are computed in passive configuration to obtain the electrotonic structure of the arborization. Steady-currents applied to the soma and expressed as a function of the path distance from the soma form different clusters of profiles in which dendritic branches are similar in voltages and current transfer effectiveness.

Activation of ryanodine receptors influences the paired-pulse depression in cultured rat hippocampal neurons.

Role of intraterminal calcium stores in modulation of short-term plasticity of evoked inhibitory postsynaptic currents (IPSCs) was studied in synaptically connected cultured hippocampal neurons using patch-clamp technique in whole-cell configuration. Currents were induced by voltage stimulation which were applied externally to presynaptic fiber. Paired stimuli resulted in paired-pulse depression (n=18) or facilitation (n=7) of the second IPSC at interpulse intervals 150 and 500 ms.

Acetylcholine-induced calcium signalling in adrenaline- and noradrenaline-containing adrenal chromaffin cells.

Adrenal chromaffin cells secrete catecholamines in response to cholinergic receptor activation by acetylcholine (ACh). Characteristics of Ca(2+) transients induced by activation of nicotinic (nAChRs) and muscarinic (mAChRs) receptors were analyzed using Fura-2 fluorescent measurements on rat chromaffin cells. We first found two populations of chromaffin cells, which differently responded on AChR stimulation.

[Intracellular calcium homeostasis in sensory neurons during hypoxia].

Hypoxia is the main reason leading to neuronal death during different forms of brain diseases. The main phenomenon observed at hypoxia is excessive growth of intraneuronal Ca2+ concentration leading to irreversible cell damage. Despite extensive studies of this process, the intracellular mechanisms responsible for disturbance in Ca2+ are still unclear.

Spatial reconfiguration of charge transfer effectiveness in active bistable dendritic arborizations.

The aim of this work was to explore the electrical spatial profile of the dendritic arborization during membrane potential oscillations of a bistable motoneuron. Computational simulations provided the spatial counterparts of the temporal dynamics of bistability and allowed simultaneous depiction the electrical states of any sites in the arborization. We assumed that the dendritic membrane had homogeneously distributed specific electrical properties and was equipped with a cocktail of passive extrasynaptic and NMDA synaptic conductances.

Imaging stochastic spatial variability of active channel clusters during excitation of single neurons.

Topographical maps of membrane voltages were obtained during action potentials by imaging, at 1 microm resolution, live dissociated neurons stained with the voltage sensitive dye RH237. We demonstrate with a theoretical approach that the spatial patterns in the images result from the distribution of net positive charges condensed in the inner sites of the membrane where clusters of open ionic channels are located. We observed that, in our biological images, this spatial distribution of open channels varies randomly from trial to trial while the action potentials recorded by the microelectrode display similar amplitudes and time-courses.

Activity-dependent reconfiguration of the effective dendritic field of motoneurons.

A neuron in vivo receives a continuous bombardment of synaptic inputs that modify the integrative properties of dendritic arborizations by changing the specific membrane resistance (R(m)). To address the mechanisms by which the synaptic background activity transforms the charge transfer effectiveness (T(x)) of a dendritic arborization, the authors simulated a neuron at rest and a highly excited neuron. After in vivo identification of the motoneurons recorded and stained intracellularly, the motoneuron arborizations were reconstructed at high spatial resolution.

Electrodiffusion of synaptic receptors: a mechanism to modify synaptic efficacy?

We analysed physical forces that act on synaptic receptor-channels following the release of neurotransmitter. These forces are: 1) electrostatic interaction between receptors, 2) stochastic Brownian diffusion in the membrane, 3) transient electric field force generated by currents through open channels, 4) viscous drag force elicited by the flowing molecules and 5) strong in-membrane friction. By considering alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type receptors, we show that, depending on the size and electrophoretic charge of the extracellular receptor domain, release of an excitatory neurotransmitter (glutamate) can induce receptor clustering towards the release site on a fast time scale (8-100 ms).

Geometry-induced features of current transfer in neuronal dendrites with tonically activated conductances.

The impact of dendritic geometry on somatopetal transfer of the current generated by steady uniform activation of excitatory synaptic conductance distributed over passive, or active (Hodgkin-Huxley type), dendrites was studied in simulated neurons. Such tonic activation was delivered to the uniform dendrite and to the dendrites with symmetric or asymmetric branching with various ratios of branch diameters. Transfer effectiveness of the dendrites with distributed sources was estimated by the core current increment directly related to the total membrane current per unit path length.