scholarly journals A homology model of the pore domain of a voltage-gated calcium channel is consistent with available SCAM data

2010 ◽  
Vol 135 (3) ◽  
pp. 261-274 ◽  
Author(s):  
Iva Bruhova ◽  
Boris S. Zhorov
Keyword(s):  
Potassium Channels ◽  
Calcium Channels ◽  
Homology Model ◽  
Ammonium Nitrogen ◽  
Sequence Alignments ◽  
Voltage Gated ◽  
Substituted Cysteine Accessibility ◽  
Local Environments ◽  
Pore Domain ◽  
Pore Lining

In the absence of x-ray structures of calcium channels, their homology models are used to rationalize experimental data and design new experiments. The modeling relies on sequence alignments between calcium and potassium channels. Zhen et al. (2005. J. Gen. Physiol. doi:10.1085/jgp.200509292) used the substituted cysteine accessibility method (SCAM) to identify pore-lining residues in the Cav2.1 channel and concluded that their data are inconsistent with the symmetric architecture of the pore domain and published sequence alignments between calcium and potassium channels. Here, we have built Kv1.2-based models of the Cav2.1 channel with 2-(trimethylammonium)ethyl methanethiosulfonate (MTSET)-modified engineered cysteines and used Monte Carlo energy minimizations to predict their energetically optimal orientations. We found that depending on the position of an engineered cysteine in S6 and S5 helices, the ammonium group in the long flexible MTSET-modified side chain can orient into the inner pore, an interface between domains (repeats), or an interface between S5 and S6 helices. Different local environments of equivalent positions in the four repeats can lead to different SCAM results. The reported current inhibition by MTSET generally decreases with the predicted distances between the ammonium nitrogen and the pore axis. A possible explanation for outliers of this correlation is suggested. Our calculations rationalize the SCAM data, validate one of several published sequence alignments between calcium and potassium channels, and suggest similar spatial dispositions of S5 and S6 helices in voltage-gated potassium and calcium channels.

scholarly journals Presynaptic Paraneoplastic Disorders of the Neuromuscular Junction: An Update

2021 ◽  
Vol 11 (8) ◽  
pp. 1035
Author(s):  
Maria Pia Giannoccaro ◽  
Patrizia Avoni ◽  
Rocco Liguori
Keyword(s):  
Potassium Channels ◽  
Neuromuscular Junction ◽  
Calcium Channels ◽  
Myasthenia Gravis ◽  
Neuromuscular Transmission ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Immune Mediated ◽  
Recent Developments ◽  
Myasthenic Syndrome

The neuromuscular junction (NMJ) is the target of a variety of immune-mediated disorders, usually classified as presynaptic and postsynaptic, according to the site of the antigenic target and consequently of the neuromuscular transmission alteration. Although less common than the classical autoimmune postsynaptic myasthenia gravis, presynaptic disorders are important to recognize due to the frequent association with cancer. Lambert Eaton myasthenic syndrome is due to a presynaptic failure to release acetylcholine, caused by antibodies to the presynaptic voltage-gated calcium channels. Acquired neuromyotonia is a condition characterized by nerve hyperexcitability often due to the presence of antibodies against proteins associated with voltage-gated potassium channels. This review will focus on the recent developments in the autoimmune presynaptic disorders of the NMJ.

scholarly journals Structures of the human two-pore domain potassium channels TREK-1 and TREK-2

2014 ◽  
Vol 70 (a1) ◽  
pp. C1489-C1489
Author(s):  
Ashley Pike ◽  
Yin Dong ◽  
Alexandra Mackenzie ◽  
Conor McClenaghan ◽  
Shubhashish Mukhopadhyay ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Channel Gating ◽  
Resting Membrane Potential ◽  
Transmembrane Helices ◽  
Ion Conductance ◽  
K2p Channels ◽  
Extracellular Stimuli ◽  
Structural Mechanisms ◽  
Pore Domain ◽  
Pore Lining

TREK-1/2 are members of the mechano-gated subfamily of two-pore (K2P) domain potassium channels leaking K+ out of the cell and contributing to the resting membrane potential. In contrast to the classical tetrameric potassium channels, K2P channels are dimeric with an atypical architecture and the structural mechanisms underlying their channel gating are poorly understood. Here we present the crystal structures of human TREK-1 and TREK-2 at resolutions of 2.7 and 3.4Å which provide insights into the basis of intracellular and extracellular gating in this unique family of ion channels. We have solved the structure of TREK-2 in two distinct conformations differing in the orientation of the pore-lining transmembrane helices. The C-terminal M4 helix is hinged at a conserved glycine residue so that it adopts one of two distinct orientations. The M4 helix is either kinked towards the membrane, packing against the M2 inner helix of the adjacent subunit ("M4 up") or straightens and interacts with the M2/M3 helices from the same subunit ("M4 down"). In the M4 down state, a hydrophobic lateral opening runs perpendicular to the ion conductance pathway between M2 and M4 and links the inner vestibule to the membrane-exposed face of the channel. Transition between the "M4 down" and "M4 up" conformations may play a role in channel activation and gating. Cocrystallisation with a TREK-1/2 channel inhibitor promotes the "M4 down" state. The structure of TREK-1 exhibits an "M4-up" conformation but is unusual in that the selectivity filter is significantly distorted with only two correctly-formed potassium sites. The structure also reveals a divalent ion binding site between the extracellular cap and the pore domain loop. The TREK-1 structure illustrates how changes at an extracellular site can affect the pore structure. The structures will be described in detail along with their implications for channel gating in response to intracellular and extracellular stimuli.

scholarly journals Panama: A tool for ion channel biophysics simulation

2018 ◽  
Author(s):  
Anuj Guruacharya
Keyword(s):  
Ion Channels ◽  
Potassium Channels ◽  
Calcium Channels ◽  
Ion Channel ◽  
Chloride Channels ◽  
High Threshold ◽  
Spreadsheet Program ◽  
Online Tool ◽  
Voltage Gated ◽  
Web App

I have created an online tool and an R library that simulates biophysics of voltage-gated ion channels. It is made publicly available as an R library called Panama at github.com/anuj2054/panama and as a web app at neuronsimulator.com. A need for such a tool was observed after surveying available software packages. I found that the available packages are either not robust enough to simulate multiple ion channels, too complicated, usable only as desktop software, not optimized for mobile devices, not interactive, lacking intuitive graphical controls, or not appropriate for undergraduate education. My app simulates the physiology of 11 different channels - voltage-gated sodium, potassium, and chloride channels; channels causing A-current, M-current, and After-HyperPolarization (AHP) current; calcium-activated potassium channels; low threshold T type calcium channels and high threshold L type calcium channels; leak sodium and leak potassium channels. It can simulate these channels under both current clamp and voltage clamp conditions. As we change the input values on the app, the output can be instantaneously visualized on the web browser and downloaded as a data table to be further analyzed in a spreadsheet program. The app is a first of its kind, mobile-friendly and touch-screen-friendly online tool that can be used to teach undergraduate neuroscience classes. It can also be used by researchers on their local computers as part of an R library. It has intuitive touch-optimized controls, instantaneous graphical output, and yet is pedagogically robust for education and casual research purposes.Neuroscience education, ion channel biophysics, Hodgkin-Huxley simulation, web app for neuroscience

scholarly journals Inhibition of Potassium Channels Affects the Ability of Pig Spermatozoa to Elicit Capacitation and Trigger the Acrosome Exocytosis Induced by Progesterone

2021 ◽  
Vol 22 (4) ◽  
pp. 1992
Author(s):  
Federico Noto ◽  
Sandra Recuero ◽  
Julián Valencia ◽  
Beatrice Saporito ◽  
Domenico Robbe ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Potassium Channels ◽  
Intracellular Calcium ◽  
Sperm Motility ◽  
Specific Inhibitor ◽  
Sperm Capacitation ◽  
Membrane Hyperpolarization ◽  
Voltage Gated ◽  
Calcium Activated Potassium Channels ◽  
Pore Domain

During capacitation, sperm undergo a myriad of changes, including remodeling of plasma membrane, modification of sperm motility and kinematic parameters, membrane hyperpolarization, increase in intracellular calcium levels, and tyrosine phosphorylation of certain sperm proteins. While potassium channels have been reported to be crucial for capacitation of mouse and human sperm, their role in pigs has not been investigated. With this purpose, sperm samples from 15 boars were incubated in capacitation medium for 300 min with quinine, a general blocker of potassium channels (including voltage-gated potassium channels, calcium-activated potassium channels, and tandem pore domain potassium channels), and paxilline (PAX), a specific inhibitor of calcium-activated potassium channels. In all samples, acrosome exocytosis was induced after 240 min of incubation with progesterone. Plasma membrane and acrosome integrity, membrane lipid disorder, intracellular calcium levels, mitochondrial membrane potential, and total and progressive sperm motility were evaluated after 0, 120, and 240 min of incubation, and after 5, 30, and 60 min of progesterone addition. Although blocking potassium channels with quinine and PAX prevented sperm to elicit in vitro capacitation by impairing motility and mitochondrial function, as well as reducing intracellular calcium levels, the extent of that inhibition was larger with quinine than with PAX. Therefore, while our data support that calcium-activated potassium channels are essential for sperm capacitation in pigs, they also suggest that other potassium channels, such as the voltage-gated, tandem pore domain, and mitochondrial ATP-regulated ones, are involved in that process. Thus, further research is needed to elucidate the specific functions of these channels and the mechanisms underlying its regulation during sperm capacitation.

scholarly journals Impact of calcium-activated potassium channels on NMDA spikes in cortical layer 5 pyramidal neurons

2016 ◽  
Vol 115 (3) ◽  
pp. 1740-1748 ◽  
Author(s):  
Tobias Bock ◽  
Greg J. Stuart
Keyword(s):  
Potassium Channels ◽  
Calcium Channels ◽  
Pyramidal Neurons ◽  
Cortical Layer ◽  
Sk Channels ◽  
Spike Generation ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Basal Dendrites ◽  
Calcium Activated Potassium Channels

Active electrical events play an important role in shaping signal processing in dendrites. As these events are usually associated with an increase in intracellular calcium, they are likely to be under the control of calcium-activated potassium channels. Here, we investigate the impact of calcium-activated potassium channels on N-methyl-d-aspartate (NMDA) receptor-dependent spikes, or NMDA spikes, evoked by glutamate iontophoresis onto basal dendrites of cortical layer 5 pyramidal neurons. We found that small-conductance calcium-activated potassium channels (SK channels) act to reduce NMDA spike amplitude but at the same time, also decrease the iontophoretic current required for their generation. This SK-mediated decrease in NMDA spike threshold was dependent on R-type voltage-gated calcium channels and indicates a counterintuitive, excitatory effect of SK channels on NMDA spike generation, whereas the capacity of SK channels to suppress NMDA spike amplitude is in line with the expected inhibitory action of potassium channels on dendritic excitability. Large-conductance calcium-activated potassium channels had no significant impact on NMDA spikes, indicating that these channels are either absent from basal dendrites or not activated by NMDA spikes. These experiments reveal complex and opposing interactions among NMDA receptors, SK channels, and voltage-gated calcium channels in basal dendrites of cortical layer 5 pyramidal neurons during NMDA spike generation, which are likely to play an important role in regulating the way these neurons integrate the thousands of synaptic inputs they receive.

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