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Voltage-gated Ion Channels (voltage-gated + ion_channel)
Selected AbstractsPhosphorylation of voltage-gated ion channels in rat olfactory receptor neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2001Christian H. Wetzel Abstract In olfactory receptor neurons (ORNs), ligand,odorant receptor interactions cause G protein-mediated activation of adenylate cyclase and a subsequent increase in concentration of the intracellular messenger cAMP. Odorant-evoked elevation in cAMP is thought to directly activate a cation-selective cyclic nucleotide-gated channel, which causes external Ca2+ influx, leading to membrane depolarization and the generation of action potentials. Our data show that in freshly dissociated rat ORNs, odorant-induced elevation in cAMP also activates cAMP-dependent protein kinase (PKA), which is then able to phosphorylate various protein targets in the olfactory signal transduction pathway, specifically voltage-gated sodium and calcium channels. The presence of PKI (PKA inhibitor peptide) blocked the modulatory action of cAMP on voltage-gated ion channels. By modulating the input/output properties of the sensory neurons, this mechanism could take part in the complex adaptation process in odorant perception. In addition, we found modulation of voltage-gated sodium and calcium channel currents by 5-hydroxytryptamine and the dopamine D1 receptor agonist SKF 38393. These findings suggest that in situ ORNs might also be a target for efferent modulation. [source] Multiple forms of activity-dependent intrinsic plasticity in layer V cortical neurones in vivoTHE JOURNAL OF PHYSIOLOGY, Issue 13 2009Jeanne T. Paz Synaptic plasticity is classically considered as the neuronal substrate for learning and memory. However, activity-dependent changes in neuronal intrinsic excitability have been reported in several learning-related brain regions, suggesting that intrinsic plasticity could also participate to information storage. Compared to synaptic plasticity, there has been little exploration of the properties of induction and expression of intrinsic plasticity in an intact brain. Here, by the means of in vivo intracellular recordings in the rat we have examined how the intrinsic excitability of layer V motor cortex pyramidal neurones is altered following brief periods of repeated firing. Changes in membrane excitability were assessed by modifications in the discharge frequency versus injected current (F,I) curves. Most (,64%) conditioned neurones exhibited a long-lasting intrinsic plasticity, which was expressed either by selective changes in the current threshold or in the slope of the F,I curve, or by concomitant changes in both parameters. These modifications in the neuronal input,output relationship led to a global increase or decrease in intrinsic excitability. Passive electrical membrane properties were unaffected by the intracellular conditioning, indicating that intrinsic plasticity resulted from modifications of voltage-gated ion channels. These results demonstrate that neocortical pyramidal neurones can express in vivo a bidirectional use-dependent intrinsic plasticity, modifying their sensitivity to weak inputs and/or the gain of their input,output function. These multiple forms of experience-dependent intrinsic changes, which expand the computational abilities of individual neurones, could shape new network dynamics and thus might participate in the formation of mnemonic motor engrams. [source] Voltage-gated proton channels: what's next?THE JOURNAL OF PHYSIOLOGY, Issue 22 2008Thomas E. DeCoursey This review is an attempt to identify and place in context some of the many questions about voltage-gated proton channels that remain unsolved. As the gene was identified only 2 years ago, the situation is very different than in fields where the gene has been known for decades. For the proton channel, most of the obvious and less obvious structure,function questions are still wide open. Remarkably, the proton channel protein strongly resembles the voltage-sensing domain of many voltage-gated ion channels, and thus offers a novel approach to study gating mechanisms. Another surprise is that the proton channel appears to function as a dimer, with two separate conduction pathways. A number of significant biological questions remain in dispute, unanswered, or in some cases, not yet asked. This latter deficit is ascribable to the intrinsic difficulty in evaluating the importance of one component in a complex system, and in addition, to the lack, until recently, of a means of performing an unambiguous lesion experiment, that is, of selectively eliminating the molecule in question. We still lack a potent, selective pharmacological inhibitor, but the identification of the gene has allowed the development of powerful new tools including proton channel antibodies, siRNA and knockout mice. [source] Subtype-selective targeting of voltage-gated sodium channelsBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2009Steve England Voltage-gated sodium channels are key to the initiation and propagation of action potentials in electrically excitable cells. Molecular characterization has shown there to be nine functional members of the family, with a high degree of sequence homology between the channels. This homology translates into similar biophysical and pharmacological properties. Confidence in some of the channels as drug targets has been boosted by the discovery of human mutations in the genes encoding a number of them, which give rise to clinical conditions commensurate with the changes predicted from the altered channel biophysics. As a result, they have received much attention for their therapeutic potential. Sodium channels represent well-precedented drug targets as antidysrhythmics, anticonvulsants and local anaesthetics provide good clinical efficacy, driven through pharmacology at these channels. However, electrophysiological characterization of clinically useful compounds in recombinant expression systems shows them to be weak, with poor selectivity between channel types. This has led to the search for subtype-selective modulators, which offer the promise of treatments with improved clinical efficacy and better toleration. Despite developments in high-throughput electrophysiology platforms, this has proven very challenging. Structural biology is beginning to offer us a greater understanding of the three-dimensional structure of voltage-gated ion channels, bringing with it the opportunity to do real structure-based drug design in the future. This discipline is still in its infancy, but developments with the expression and purification of prokaryotic sodium channels offer the promise of structure-based drug design in the not too distant future. [source] | ||||||||||