scholarly journals A comprehensive review of peptide toxins vs synthetic modulators of BK channels in Epilepsy

2021 ◽  
Vol 5 (05) ◽  
pp. 01-07
Author(s):  
Naveena Lavanya Latha Jeevigunta ◽  
E. Susithra ◽  
Gouthami Thumma ◽  
MV. Basaveswara Rao ◽  
Kiran Gangarapu
Keyword(s):  
Neuronal Excitability ◽  
Bk Channels ◽  
Bk Channel ◽  
Molecular Formula ◽  
Channel Blockers ◽  
Binding Interface ◽  
Formation Pattern ◽  
Neuronal Disease ◽  
Functional Consequences ◽  
Peptide Toxins

BK channels, or voltage-gated Ca2+ channels, are essential regulators of neuronal excitability and muscular contractions, all of which are abnormal in epilepsy, a chronic neuronal disease. The form, frequency, and transmission of action potentials (APs), as well as neurotransmitter release from presynaptic terminals, are all influenced by BK channels found in the plasma membrane of neurons. Over the last two decades, several naturally occurring BK channel modulators have attracted a lot of attention. The structural and pharmacological properties of BK channel blockers are discussed in this article. The properties of various venom peptide toxins from scorpions and snakes are first identified, with a focus on their distinctive structural motifs, such as their disulfide bond formation pattern, the binding interface between the toxin and the BK channel, and the functional consequences of the toxins' blockage of BK channels. Then, several non-peptide BK channel blockers are discussed, along with their molecular formula and pharmacological impact on BK channels. The precise categorization and explanations of these BK channel blockers are hoped to provide mechanistic insights into BK channel blockade. The structures of peptide toxins and non-peptide compounds may serve as models for the development of new channel blockers, as well as aid in the optimization of lead compounds for use in neurological disorders.

scholarly journals Selectivity filter gating in large-conductance Ca2+-activated K+ channels

2012 ◽  
Vol 139 (3) ◽  
pp. 235-244 ◽  
Author(s):  
Jill Thompson ◽  
Ted Begenisich
Keyword(s):  
Bk Channels ◽  
Bk Channel ◽  
Selectivity Filter ◽  
Channel Blockers ◽  
Intracellular Location ◽  
K Channels ◽  
Kv Channels ◽  
Quaternary Ammonium Ions ◽  
Tetrabutyl Ammonium ◽  
Opposite Behavior

Membrane voltage controls the passage of ions through voltage-gated K (Kv) channels, and many studies have demonstrated that this is accomplished by a physical gate located at the cytoplasmic end of the pore. Critical to this determination were the findings that quaternary ammonium ions and certain peptides have access to their internal pore-blocking sites only when the channel gates are open, and that large blocking ions interfere with channel closing. Although an intracellular location for the physical gate of Kv channels is well established, it is not clear if such a cytoplasmic gate exists in all K+ channels. Some studies on large-conductance, voltage- and Ca2+-activated K+ (BK) channels suggest a cytoplasmic location for the gate, but other findings question this conclusion and, instead, support the concept that BK channels are gated by the pore selectivity filter. If the BK channel is gated by the selectivity filter, the interactions between the blocking ions and channel gating should be influenced by the permeant ion. Thus, we tested tetrabutyl ammonium (TBA) and the Shaker “ball” peptide (BP) on BK channels with either K+ or Rb+ as the permeant ion. When tested in K+ solutions, both TBA and the BP acted as open-channel blockers of BK channels, and the BP interfered with channel closing. In contrast, when Rb+ replaced K+ as the permeant ion, TBA and the BP blocked both closed and open BK channels, and the BP no longer interfered with channel closing. We also tested the cytoplasmically gated Shaker K channels and found the opposite behavior: the interactions of TBA and the BP with these Kv channels were independent of the permeant ion. Our results add significantly to the evidence against a cytoplasmic gate in BK channels and represent a positive test for selectivity filter gating.

scholarly journals N-terminal Inactivation Domains of β Subunits Are Protected from Trypsin Digestion by Binding within the Antechamber of BK Channels

2009 ◽  
Vol 133 (3) ◽  
pp. 263-282 ◽  
Author(s):  
Zhe Zhang ◽  
Xu-Hui Zeng ◽  
Xiao-Ming Xia ◽  
Christopher J. Lingle
Keyword(s):  
Bk Channels ◽  
Bk Channel ◽  
Channel Blockers ◽  
Closed Channel ◽  
Central Cavity ◽  
Pore Blocking ◽  
N Terminus ◽  
Channel Conditions ◽  
Speed Up ◽  
Auxiliary Β Subunits

N termini of auxiliary β subunits that produce inactivation of large-conductance Ca2+-activated K+ (BK) channels reach their pore-blocking position by first passing through side portals into an antechamber separating the BK pore module and the large C-terminal cytosolic domain. Previous work indicated that the β2 subunit inactivation domain is protected from digestion by trypsin when bound in the inactivated conformation. Other results suggest that, even when channels are closed, an inactivation domain can also be protected from digestion by trypsin when bound within the antechamber. Here, we provide additional tests of this model and examine its applicability to other β subunit N termini. First, we show that specific mutations in the β2 inactivation segment can speed up digestion by trypsin under closed-channel conditions, supporting the idea that the β2 N terminus is protected by binding within the antechamber. Second, we show that cytosolic channel blockers distinguish between protection mediated by inactivation and protection under closed-channel conditions, implicating two distinct sites of protection. Together, these results confirm the idea that β2 N termini can occupy the BK channel antechamber by interaction at some site distinct from the BK central cavity. In contrast, the β3a N terminus is digested over 10-fold more quickly than the β2 N terminus. Analysis of factors that contribute to differences in digestion rates suggests that binding of an N terminus within the antechamber constrains the trypsin accessibility of digestible basic residues, even when such residues are positioned outside the antechamber. Our analysis indicates that up to two N termini may simultaneously be protected from digestion. These results indicate that inactivation domains have sites of binding in addition to those directly involved in inactivation.

scholarly journals KCNMA1-Linked Channelopathy

2019 ◽  
Author(s):  
Cole S Bailey ◽  
Hans J Moldenhauer ◽  
Su Mi Park ◽  
Sotirios Keros ◽  
Andrea L Meredith
Keyword(s):  
Neuronal Excitability ◽  
De Novo ◽  
Phenotypic Variability ◽  
Bk Channels ◽  
Bk Channel ◽  
Loss Of Function ◽  
Current Standard ◽  
Α Subunit ◽  
Specific Patient ◽  
Organ Systems

KCNMA1 encodes the pore-forming α subunit of the ‘Big K+’ (BK) large conductance calcium and voltage-activated K+ channel (KCa1.1). BK channels are widely distributed across many tissues, including both excitable and non-excitable cells. Expression levels are highest in brain and muscle, where the channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1–/–) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles for BK channels in animal models, the consequences of dysfunctional BK channels in humans is not well-characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as ‘KCNMA1-linked channelopathy.’ These mutations encompass gain of function (GOF) and loss of function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal non-kinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date, and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1­­-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

scholarly journals KCNMA1-linked channelopathy

2019 ◽  
Author(s):  
Cole S Bailey ◽  
Hans J Moldenhauer ◽  
Su Mi Park ◽  
Sotirios Keros ◽  
Andrea L Meredith
Keyword(s):  
Neuronal Excitability ◽  
De Novo ◽  
Phenotypic Variability ◽  
Bk Channels ◽  
Bk Channel ◽  
Loss Of Function ◽  
Current Standard ◽  
Α Subunit ◽  
Specific Patient ◽  
Organ Systems

KCNMA1 encodes the pore-forming α subunit of the ‘Big K+’ (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and non-excitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1–/–) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well-characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as ‘KCNMA1-linked channelopathy.’ These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal non-kinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date, and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1­­-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

scholarly journals Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Oscar Vivas ◽  
Claudia M Moreno ◽  
Luis F Santana ◽  
Bertil Hille
Keyword(s):  
Single Molecule ◽  
Neuronal Excitability ◽  
Low Voltage ◽  
Calcium Influx ◽  
Sympathetic Neurons ◽  
Spatial Arrangement ◽  
Bk Channels ◽  
Bk Channel ◽  
Functional Coupling ◽  
Channel Activation

CaV-channel dependent activation of BK channels is critical for feedback control of both calcium influx and cell excitability. Here we addressed the functional and spatial interaction between BK and CaV1.3 channels, unique CaV1 channels that activate at low voltages. We found that when BK and CaV1.3 channels were co-expressed in the same cell, BK channels started activating near −50 mV, ~30 mV more negative than for activation of co-expressed BK and high-voltage activated CaV2.2 channels. In addition, single-molecule localization microscopy revealed striking clusters of CaV1.3 channels surrounding clusters of BK channels and forming a multi-channel complex both in a heterologous system and in rat hippocampal and sympathetic neurons. We propose that this spatial arrangement allows tight tracking between local BK channel activation and the gating of CaV1.3 channels at quite negative membrane potentials, facilitating the regulation of neuronal excitability at voltages close to the threshold to fire action potentials.

scholarly journals Role of epoxyeicosatrienoic acids as autocrine metabolites in glutamate-mediated K+ signaling in perivascular astrocytes

2010 ◽  
Vol 299 (5) ◽  
pp. C1068-C1078 ◽  
Author(s):  
Haruki Higashimori ◽  
Víctor M. Blanco ◽  
Vengopal Raju Tuniki ◽  
John R. Falck ◽  
Jessica A. Filosa
Keyword(s):  
Bk Channels ◽  
Bk Channel ◽  
Epoxyeicosatrienoic Acids ◽  
Channel Blockers ◽  
Open Probability ◽  
Endogenous Production ◽  
Outward Currents ◽  
Intracellular Ca ◽  
Induced Currents

Epoxyeicosatrienoic acids (EETs), synthesized and released by astrocytes in response to glutamate, are known to play a pivotal role in neurovascular coupling. In vascular smooth muscle cells (VSMC), EETs activate large-conductance, Ca2+-activated K+ (BK) channels resulting in hyperpolarization and vasodilation. However, the functional role and mechanism of action for glial-derived EETs are still to be determined. In this study, we evaluated the effect of the synthetic EET analog 11-nonyloxy-undec-8(Z)-enoic acid (NUD-GA) on outward K+ currents mediated by calcium-activated K+ channels. Addition of NUD-GA significantly increased intracellular Ca2+ and outward K+ currents in perivascular astrocytes. NUD-GA-induced currents were significantly inhibited by BK channel blockers paxilline and tetraethylammonium (TEA) (23.4 ± 2.4%; P < 0.0005). Similarly, NUD-GA-induced currents were also significantly inhibited in the presence of the small-conductance Ca2+-activated K+ channel inhibitor apamin along with a combination of blockers against glutamate receptors (12.8 ± 2.70%; P < 0.05). No changes in outward currents were observed in the presence of the channel blocker for intermediate-conductance K+ channels TRAM-34. Blockade of the endogenous production of EETs with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) significantly blunted ( dl)-1-aminocyclopentane-trans-1,3-dicarboxylic acid ( t-ACPD)-induced outward K+ currents ( P < 0.05; n = 6). Both NUD-GA and t-ACPD significantly increased BK channel single open probability; the later was blocked following MS-PPOH incubation. Our data supports the idea that EETs are potent K+ channel modulators in cortical perivascular astrocytes and further suggest that these metabolites may participate in NVC by modulating the levels of K+ released at the gliovascular space.

scholarly journals BK potassium currents contribute differently to action potential waveform and firing rate as rat hippocampal neurons mature in the first postnatal week

2020 ◽  
Vol 124 (3) ◽  
pp. 703-714
Author(s):  
Michael S. Hunsberger ◽  
Michelle Mynlieff
Keyword(s):  
Action Potential ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Expression Patterns ◽  
Bk Channels ◽  
Bk Channel ◽  
Developmental Trends ◽  
Action Potential Waveform ◽  
Early Developmental ◽  
Potential Waveform

This work describes the early developmental trends of large-conductance calcium-activated potassium (BK) channel activity. Early developmental trends in expression of BK channels, both total expression and relative isoform expression, have been previously reported, but little work describes the effect of these changes in expression patterns on excitability. Here, we show that early changes in BK channel expression patterns lead to changes in the role of BK channels in determining the action potential waveform and neuronal excitability.

scholarly journals Potassium channel dysfunction in human neuronal models of Angelman syndrome

Science ◽  
2019 ◽  
Vol 366 (6472) ◽  
pp. 1486-1492 ◽  
Author(s):  
Alfred Xuyang Sun ◽  
Qiang Yuan ◽  
Masahiro Fukuda ◽  
Weonjin Yu ◽  
Haidun Yan ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Neuronal Excitability ◽  
Bk Channels ◽  
Bk Channel ◽  
Abnormal Behavior ◽  
Channel Activity ◽  
Ubiquitin Protein Ligase ◽  
Human Neurons ◽  
Voltage Dependent ◽  
Human And Mouse

Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.

scholarly journals KCNMA1-linked channelopathy

2019 ◽  
Author(s):  
Cole S Bailey ◽  
Hans J Moldenhauer ◽  
Su Mi Park ◽  
Sotirios Keros ◽  
Andrea L Meredith
Keyword(s):  
Neuronal Excitability ◽  
De Novo ◽  
Phenotypic Variability ◽  
Bk Channels ◽  
Bk Channel ◽  
Loss Of Function ◽  
Current Standard ◽  
Α Subunit ◽  
Specific Patient ◽  
Organ Systems

KCNMA1 encodes the pore-forming α subunit of the ‘Big K+’ (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and non-excitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1–/–) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well-characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as ‘KCNMA1-linked channelopathy.’ These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal non-kinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date, and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1­­-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.

scholarly journals An ensemble of toxic channel types underlies the severity of the de novo variant G375R of the human BK channel

2021 ◽  
Author(s):  
Yanyan Geng ◽  
Ping Li ◽  
Alice Butler ◽  
Bill Wang ◽  
Lawrence Salkoff ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
De Novo ◽  
Bk Channels ◽  
Bk Channel ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
De Novo Mutations ◽  
Negative Effect ◽  
De Novo Variant ◽  
Heteromeric Channels

De novo mutations play a prominent role in neurodevelopmental diseases including autism, schizophrenia, and intellectual disability. Many de novo mutations are dominant and so severe that the afflicted individuals do not reproduce, so the mutations are not passed into the general population. For multimeric proteins, such severity may result from a dominant-negative effect where mutant subunits assemble with WT to produce channels with adverse properties. Here we study the de novo variant G375R heterozygous with the WT allele for the large conductance voltage- and Ca2+-activated potassium (BK) channel, Slo1. This variant has been reported to produce devastating neurodevelopmental disorders in three unrelated children. If mutant and WT subunits assemble randomly to form tetrameric BK channels, then ~6% of the assembled channels would be wild type (WT), ~88% would be heteromeric incorporating from 1-3 mutant subunits per channel, and ~6% would be homomeric mutant channels consisting of four mutant subunits. To test this hypothesis, we analyzed the biophysical properties of single BK channels in the ensemble of channels expressed following a 1:1 injection of mutant and WT cRNA into oocytes. We found ~3% were WT channels, ~85% were heteromeric channels, and ~12% were homomeric mutant channels. All of the heteromeric channels as well as the homomeric mutant channels displayed toxic properties, indicating a dominant negative effect of the mutant subunits. The toxic channels were open at inappropriate negative voltages, even in the absence of Ca2+, which would lead to altered cellular function and decreased neuronal excitability.

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