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Neuroscience_topics
Neuroscience: CNS disease, pain, brain research, ion channels, synaptic transmission, channelopathies, neuronal network
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Scooped by Julien Hering, PhD
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Structural basis for Ca2+ selectivity of a voltage-gated calcium channel

Structural basis for Ca2+ selectivity of a voltage-gated calcium channel | Neuroscience_topics | Scoop.it

Voltage-gated calcium (CaV) channels catalyse rapid, highly selective influx of Ca2+ into cells despite a 70-fold higher extracellular concentration of Na+. How CaV channels solve this fundamental biophysical problem remains unclear. Here we report physiological and crystallographic analyses of a calcium selectivity filter constructed in the homotetrameric bacterial NaV channel NaVAb. Our results reveal interactions of hydrated Ca2+ with two high-affinity Ca2+-binding sites followed by a third lower-affinity site that would coordinate Ca2+ as it moves inward. At the selectivity filter entry, Site 1 is formed by four carboxyl side chains, which have a critical role in determining Ca2+ selectivity. Four carboxyls plus four backbone carbonyls form Site 2, which is targeted by the blocking cations Cd2+ and Mn2+, with single occupancy. The lower-affinity Site 3 is formed by four backbone carbonyls alone, which mediate exit into the central cavity. This pore architecture suggests a conduction pathway involving transitions between two main states with one or two hydrated Ca2+ ions bound in the selectivity filter and supports a ‘knock-off’ mechanism of ion permeation through a stepwise-binding process. The multi-ion selectivity filter of our CaVAb model establishes a structural framework for understanding the mechanisms of ion selectivity and conductance by vertebrate CaV channels. (...) - by Tang et al.Nature 505, 56–61 (02 January 2014)

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The Mechanism of Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels Based on Molecular Dynamics Simulation

The Mechanism of Na+/K+ Selectivity in Mammalian Voltage-Gated Sodium Channels Based on Molecular Dynamics Simulation | Neuroscience_topics | Scoop.it

Voltage-gated sodium (Nav) channels and their Na+/K+ selectivity are of great importance in the mammalian neuronal signaling. According to mutational analysis, the Na+/K+ selectivity in mammalian Nav channels is mainly determined by the Lys and Asp/Glu residues located at the constriction site within the selectivity filter. Despite successful molecular dynamics simulations conducted on the prokaryotic Nav channels, the lack of Lys at the constriction site of prokaryotic Nav channels limits how much can be learned about the Na+/K+selectivity in mammalian Nav channels. In this work, we modeled the mammalian Nav channel by mutating the key residues at the constriction site in a prokaryotic Nav channel (NavRh) to its mammalian counterpart. By simulating the mutant structure, we found that the Na+ preference in mammalian Nav channels is collaboratively achieved by the deselection from Lys and the selection from Asp/Glu within the constriction site. - by XIA M et al., Biophysical JournalVolume 104, Issue 11, 4 June 2013, Pages 2401–2409

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Water molecules control inactivation and recovery of potassium channels

Water molecules control inactivation and recovery of potassium channels | Neuroscience_topics | Scoop.it

Just 12 molecules of water cause the long post-activation recovery period required by potassium ion channels before they can function again. Using molecular simulations that modeled a potassium channel and its immediate cellular environment, atom for atom, University of Chicago scientists have revealed this new mechanism in the function of a nearly universal biological structure, with implications ranging from fundamental biology to the design of pharmaceuticals. (...) - ScienceDaily, July 28, 2013

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The Omega Current

The Omega Current | Neuroscience_topics | Scoop.it

Mutation of voltage-sensor domains (VSDs) can sometimes lead to ions leaking across the membrane through the VSDs themselves. Ion conduction through the mutated VSD of the Shaker Kv channel was coined the “omega current” in 2005 by Tombola, Pathak and Isacoff (Tombola et al., 2005). Many different mutations have been identified that result in current leaking through VSDs in many different channels. This current can be carried by a variety of ions including H+, Li+, K+, Cs+ and guanidinium. (...) lettsscience on July 24, 2012

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