scholarly journals Oligodendrocytes, BK channels and remyelination

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 781
Author(s):  
Maddalena Rupnik ◽  
David Baker ◽  
David L. Selwood
Keyword(s):  
Demyelinating Disease ◽  
Bk Channels ◽  
Bk Channel ◽  
Neurological Disability ◽  
Excitatory Neurotransmitter ◽  
Neuronal Excitation ◽  
Current Therapies ◽  
The Central Nervous System ◽  
Immunomodulatory Therapies

Oligodendrocytes wrap multiple lamellae of their membrane, myelin, around axons of the central nervous system (CNS), to improve impulse conduction. Myelin synthesis is specialised and dynamic, responsive to local neuronal excitation. Subtle pathological insults are sufficient to cause significant neuronal metabolic impairment, so myelin preservation is necessary to safeguard neural networks. Multiple sclerosis (MS) is the most prevalent demyelinating disease of the CNS. In MS, inflammatory attacks against myelin, proposed to be autoimmune, cause myelin decay and oligodendrocyte loss, leaving neurons vulnerable. Current therapies target the prominent neuroinflammation but are mostly ineffective in protecting from neurodegeneration and the progressive neurological disability. People with MS have substantially higher levels of extracellular glutamate, the main excitatory neurotransmitter. This impairs cellular homeostasis to cause excitotoxic stress. Large conductance Ca2+-activated K+ channels (BK channels) could preserve myelin or allow its recovery by protecting cells from the resulting excessive excitability. This review evaluates the role of excitotoxic stress, myelination and BK channels in MS pathology, and explores the hypothesis that BK channel activation could be a therapeutic strategy to protect oligodendrocytes from excitotoxic stress in MS. This could reduce progression of neurological disability if used in parallel to immunomodulatory therapies.

scholarly journals Oligodendrocytes, BK channels and the preservation of myelin

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 781
Author(s):  
Maddalena Rupnik ◽  
David Baker ◽  
David L. Selwood
Keyword(s):  
Demyelinating Disease ◽  
Bk Channels ◽  
Bk Channel ◽  
Neurological Disability ◽  
Excitatory Neurotransmitter ◽  
Neuronal Excitation ◽  
Current Therapies ◽  
The Central Nervous System ◽  
Immunomodulatory Therapies

Oligodendrocytes wrap multiple lamellae of their membrane, myelin, around axons of the central nervous system (CNS), to improve impulse conduction. Myelin synthesis is specialised and dynamic, responsive to local neuronal excitation. Subtle pathological insults are sufficient to cause significant neuronal metabolic impairment, so myelin preservation is necessary to safeguard neural networks. Multiple sclerosis (MS) is the most prevalent demyelinating disease of the CNS. In MS, inflammatory attacks against myelin, proposed to be autoimmune, cause myelin decay and oligodendrocyte loss, leaving neurons vulnerable. Current therapies target the prominent neuroinflammation but are mostly ineffective in protecting from neurodegeneration and the progressive neurological disability. People with MS have substantially higher levels of extracellular glutamate, the main excitatory neurotransmitter. This impairs cellular homeostasis to cause excitotoxic stress. Large conductance Ca2+-activated K+ channels (BK channels) could preserve myelin or allow its recovery by protecting cells from the resulting excessive excitability. This review evaluates the role of excitotoxic stress, myelination and BK channels in MS pathology, and explores the hypothesis that BK channel activation could be a therapeutic strategy to protect oligodendrocytes from excitotoxic stress in MS. This could reduce progression of neurological disability if used in parallel to immunomodulatory therapies.

The Yin and Yang of BK Channels in Epilepsy

2018 ◽  
Vol 17 (4) ◽  
pp. 272-279 ◽  
Author(s):  
Yudan Zhu ◽  
Shuzhang Zhang ◽  
Yijun Feng ◽  
Qian Xiao ◽  
Jiwei Cheng ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Bk Channels ◽  
Bk Channel ◽  
Potential Shape ◽  
Yin And Yang ◽  
The Central Nervous System ◽  
Action Potential Shape ◽  
Excitability Of Neurons

Background & Objective: The large conductance calcium-activated potassium (BK) channel, extensively distributed in the central nervous system (CNS), is considered as a vital player in the pathogenesis of epilepsy, with evidence implicating derangement of K+ as well as regulating action potential shape and duration. However, unlike other channels implicated in epilepsy whose function in neurons could clearly be labeled “excitatory” or “inhibitory”, the unique physiological behavior of the BK channel allows it to both augment and decrease the excitability of neurons. Thus, the role of BK in epilepsy is controversial so far, and a growing area of intense investigation. Conclusion: Here, this review aims to highlight recent discoveries on the dichotomous role of BK channels in epilepsy, focusing on relevant BK-dependent pro- as well as antiepileptic pathways, and discuss the potential of BK specific modulators for the treatment of epilepsy.

scholarly journals Regulatory γ1 subunits defy symmetry in functional modulation of BK channels

2018 ◽  
Vol 115 (40) ◽  
pp. 9923-9928 ◽  
Author(s):  
Vivian Gonzalez-Perez ◽  
Manu Ben Johny ◽  
Xiao-Ming Xia ◽  
Christopher J. Lingle
Keyword(s):  
Single Channel ◽  
Regulatory Protein ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Bk Channels ◽  
Bk Channel ◽  
Single Type ◽  
Regulatory Subunits ◽  
And Function

Structural symmetry is a hallmark of homomeric ion channels. Nonobligatory regulatory proteins can also critically define the precise functional role of such channels. For instance, the pore-forming subunit of the large conductance voltage and calcium-activated potassium (BK, Slo1, or KCa1.1) channels encoded by a single KCa1.1 gene assembles in a fourfold symmetric fashion. Functional diversity arises from two families of regulatory subunits, β and γ, which help define the range of voltages over which BK channels in a given cell are activated, thereby defining physiological roles. A BK channel can contain zero to four β subunits per channel, with each β subunit incrementally influencing channel gating behavior, consistent with symmetry expectations. In contrast, a γ1 subunit (or single type of γ1 subunit complex) produces a functionally all-or-none effect, but the underlying stoichiometry of γ1 assembly and function remains unknown. Here we utilize two distinct and independent methods, a Forster resonance energy transfer-based optical approach and a functional reporter in single-channel recordings, to reveal that a BK channel can contain up to four γ1 subunits, but a single γ1 subunit suffices to induce the full gating shift. This requires that the asymmetric association of a single regulatory protein can act in a highly concerted fashion to allosterically influence conformational equilibria in an otherwise symmetric K+channel.

scholarly journals Excitatory amino acid transporters tonically restrain nTS synaptic and neuronal activity to modulate cardiorespiratory function

2016 ◽  
Vol 115 (3) ◽  
pp. 1691-1702 ◽  
Author(s):  
Michael P. Matott ◽  
Brian C. Ruyle ◽  
Eileen M. Hasser ◽  
David D. Kline
Keyword(s):  
Amino Acid ◽  
Excitatory Amino Acid ◽  
Visceral Afferents ◽  
Amino Acid Transporters ◽  
Excitatory Amino Acid Transporters ◽  
Excitatory Neurotransmitter ◽  
Extracellular Milieu ◽  
Cardiorespiratory Function ◽  
The Central Nervous System

The nucleus tractus solitarii (nTS) is the initial central termination site for visceral afferents and is important for modulation and integration of multiple reflexes including cardiorespiratory reflexes. Glutamate is the primary excitatory neurotransmitter in the nTS and is removed from the extracellular milieu by excitatory amino acid transporters (EAATs). The goal of this study was to elucidate the role of EAATs in the nTS on basal synaptic and neuronal function and cardiorespiratory regulation. The majority of glutamate clearance in the central nervous system is believed to be mediated by astrocytic EAAT 1 and 2. We confirmed the presence of EAAT 1 and 2 within the nTS and their colocalization with astrocytic markers. EAAT blockade with dl- threo-β-benzyloxyaspartic acid (TBOA) produced a concentration-related depolarization, increased spontaneous excitatory postsynaptic current (EPSC) frequency, and enhanced action potential discharge in nTS neurons. Solitary tract-evoked EPSCs were significantly reduced by EAAT blockade. Microinjection of TBOA into the nTS of anesthetized rats induced apneic, sympathoinhibitory, depressor, and bradycardic responses. These effects mimicked the response to microinjection of exogenous glutamate, and glutamate responses were enhanced by EAAT blockade. Together these data indicate that EAATs tonically restrain nTS excitability to modulate cardiorespiratory function.

Multiple sclerosis attacks are associated with picornavirus infections

2004 ◽  
Vol 10 (2) ◽  
pp. 145-148 ◽  
Author(s):  
John D Kriesel ◽  
Andrea White ◽  
Frederick G Hayden ◽  
S L Spruance ◽  
Jack Petajan
Keyword(s):  
Multiple Sclerosis ◽  
At Risk ◽  
Demyelinating Disease ◽  
Respiratory Infections ◽  
Risk Period ◽  
Relapsing Remitting ◽  
The Central Nervous System ◽  
Upper Respiratory ◽  
Polymerase Chain

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system, which often follows a relapsing-remitting (RR) course with discrete attacks. MS attacks have been associated with upper respiratory infections (URIs), but the specific viruses responsible have not been identified. We studied a cohort of 16 RRMS patients experiencing URI and followed them for clinically identifiable attacks. The viral causes of 21 separate URIs were investigated using culture and polymerase chain reactio n (PCR) of nasal swab specimens, and by serology. Sibley’s ‘at-risk’ period for MS attacks, beginning two weeks before and continuing for five weeks after a URI, was used for the analysis. Seven of the nine (78%) URIs due to picornaviruses were associated with an MS attack during the at-risk period. By contrast, only two of 12 (17%) picornavirus-negative URIs were associated with an MS attack (P =0.01). The possible role of picornaviruses in the patho genesis of MS deserves further study.

scholarly journals Position and Role of the BK Channel α Subunit S0 Helix Inferred from Disulfide Crosslinking

2008 ◽  
Vol 131 (6) ◽  
pp. 537-548 ◽  
Author(s):  
Guoxia Liu ◽  
Sergey I. Zakharov ◽  
Lin Yang ◽  
Shi-Xian Deng ◽  
Donald W. Landry ◽  
...  
Keyword(s):  
Bk Channels ◽  
Bk Channel ◽  
Electrostatic Energy ◽  
Extracellular Loop ◽  
Membrane Domain ◽  
Α Subunit ◽  
Disulfide Crosslinking ◽  
Gating Charge ◽  
Sensor Activation

The position and role of the unique N-terminal transmembrane (TM) helix, S0, in large-conductance, voltage- and calcium-activated potassium (BK) channels are undetermined. From the extents of intra-subunit, endogenous disulfide bond formation between cysteines substituted for the residues just outside the membrane domain, we infer that the extracellular flank of S0 is surrounded on three sides by the extracellular flanks of TM helices S1 and S2 and the four-residue extracellular loop between S3 and S4. Eight different double cysteine–substituted alphas, each with one cysteine in the S0 flank and one in the S3–S4 loop, were at least 90% disulfide cross-linked. Two of these alphas formed channels in which 90% cross-linking had no effect on the V50 or on the activation and deactivation rate constants. This implies that the extracellular ends of S0, S3, and S4 are close in the resting state and move in concert during voltage sensor activation. The association of S0 with the gating charge bearing S3 and S4 could contribute to the considerably larger electrostatic energy required to activate the BK channel compared with typical voltage-gated potassium channels with six TM helices.

scholarly journals Antecedent hydrogen sulfide elicits an anti-inflammatory phenotype in postischemic murine small intestine: role of BK channels

2010 ◽  
Vol 299 (5) ◽  
pp. H1554-H1567 ◽  
Author(s):  
Mozow Y. Zuidema ◽  
Yan Yang ◽  
Meifang Wang ◽  
Theodore Kalogeris ◽  
Yajun Liu ◽  
...  
Keyword(s):  
Small Intestine ◽  
Hydrogen Sulfide ◽  
Ischemia Reperfusion ◽  
Bk Channels ◽  
Bk Channel ◽  
Confocal Imaging ◽  
Sodium Hydrosulfide ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

The objectives of this study were to determine the role of calcium-activated, small (SK), intermediate (IK), and large (BK) conductance potassium channels in initiating the development of an anti-inflammatory phenotype elicited by preconditioning with an exogenous hydrogen sulfide (H2S) donor, sodium hydrosulfide (NaHS). Intravital microscopy was used to visualize rolling and firmly adherent leukocytes in vessels of the small intestine of mice preconditioned with NaHS (in the absence and presence of SK, IK, and BK channel inhibitors, apamin, TRAM-34, and paxilline, respectively) or SK/IK (NS-309) or BK channel activators (NS-1619) 24 h before ischemia-reperfusion (I/R). I/R induced marked increases in leukocyte rolling and adhesion, effects that were largely abolished by preconditioning with NaHS, NS-309, or NS-1619. The postischemic anti-inflammatory effects of NaHS-induced preconditioning were mitigated by BKB channel inhibitor treatment coincident with NaHS, but not by apamin or TRAM-34, 24 h before I/R. Confocal imaging and immunohistochemistry were used to demonstrate the presence of BKα subunit staining in both endothelial and vascular smooth muscle cells of isolated, pressurized mesenteric venules. Using patch-clamp techniques, we found that BK channels in cultured endothelial cells were activated after exposure to NaHS. Bath application of the same concentration of NaHS used in preconditioning protocols led to a rapid increase in a whole cell K+ current; specifically, the component of K+ current blocked by the selective BK channel antagonist iberiotoxin. The activation of BK current by NaHS could also be demonstrated in single channel recording mode where it was independent of a change in intracellular Ca+ concentration. Our data are consistent with the concept that H2S induces the development of an anti-adhesive state in I/R in part mediated by a BK channel-dependent mechanism.

scholarly journals Stimulation of β3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+-activated K+ channels

2008 ◽  
Vol 295 (5) ◽  
pp. C1344-C1353 ◽  
Author(s):  
Kiril L. Hristov ◽  
Xiangli Cui ◽  
Sean M. Brown ◽  
Lei Liu ◽  
Whitney F. Kellett ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Urinary Bladder ◽  
Bk Channels ◽  
Bk Channel ◽  
Bladder Smooth Muscle ◽  
Rat Urinary Bladder ◽  
Urinary Bladder Smooth Muscle ◽  
Brl 37344 ◽  
Stimulation Of

We investigated the role of large-conductance Ca2+-activated K+ (BK) channels in β3-adrenoceptor (β3-AR)-induced relaxation in rat urinary bladder smooth muscle (UBSM). BRL 37344, a specific β3-AR agonist, inhibits spontaneous contractions of isolated UBSM strips. SR59230A, a specific β3-AR antagonist, and H89, a PKA inhibitor, reduced the inhibitory effect of BRL 37344. Iberiotoxin, a specific BK channel inhibitor, shifts the BRL 37344 concentration response curves for contraction amplitude, net muscle force, and tone to the right. Freshly dispersed UBSM cells and the perforated mode of the patch-clamp technique were used to determine further the role of β3-AR stimulation by BRL 37344 on BK channel activity. BRL 37344 increased spontaneous, transient, outward BK current (STOC) frequency by 46.0 ± 20.1%. In whole cell mode at a holding potential of Vh = 0 mV, the single BK channel amplitude was 5.17 ± 0.28 pA, whereas in the presence of BRL 37344, it was 5.55 ± 0.41 pA. The BK channel open probability was also unchanged. In the presence of ryanodine and nifedipine, the current-voltage relationship in response to depolarization steps in the presence and absence of BRL 37344 was identical. In current-clamp mode, BRL 37344 caused membrane potential hyperpolarization from −26.1 ± 2.1 mV (control) to −29.0 ± 2.2 mV. The BRL 37344-induced hyperpolarization was eliminated by application of iberiotoxin, tetraethylammonium or ryanodine. The data indicate that stimulation of β3-AR relaxes rat UBSM by increasing the BK channel STOC frequency, which causes membrane hyperpolarization and thus relaxation.

scholarly journals A Review of Vascular Disease Risk Factors and Multiple Sclerosis

US Neurology ◽  
2017 ◽  
Vol 13 (02) ◽  
pp. 90
Author(s):  
Meena R Kannan ◽  
Vijayshree Yadav ◽  
◽  
Keyword(s):  
Risk Factors ◽  
Multiple Sclerosis ◽  
Vascular Disease ◽  
Type Ii Diabetes ◽  
Demyelinating Disease ◽  
Disease Risk ◽  
Current Knowledge ◽  
Type Ii Diabetes Mellitus ◽  
The Central Nervous System

Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system and the most common non-traumatic cause of disability in young adults. Recent research shows that vascular disease risk factors (VDRFs) such as obesity, smoking, hyperlipidemia, hypertension, type II diabetes mellitus, and metabolic syndrome, can influence MS on its onset, disease activity, progression, and resultant disability. This review evaluates the current knowledge on the role of VDRFs on outcomes among people with MS (PwMS) and shows that while VDRF prevalence may or may not be higher among PwMS compared with the general population, its presence can influence MS in myriad ways. Management of VDRFs through early detection and treatment may be a promising approach to improving outcomes in PwMS.

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