scholarly journals BK Channel Gating Mechanisms: Progresses Toward a Better Understanding of Variants Linked Neurological Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Jianmin Cui
Keyword(s):  
Neurological Disorders ◽  
Recent Progress ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Bk Channels ◽  
Bk Channel ◽  
Channel Activation ◽  
Gating Mechanisms ◽  
Intracellular Ca ◽  
Atomistic Structure

The large conductance Ca2+-activated potassium (BK) channel is activated by both membrane potential depolarization and intracellular Ca2+ with distinct mechanisms. Neural physiology is sensitive to the function of BK channels, which is shown by the discoveries of neurological disorders that are associated with BK channel mutations. This article reviews the molecular mechanisms of BK channel activation in response to voltage and Ca2+ binding, including the recent progress since the publication of the atomistic structure of the whole BK channel protein, and the neurological disorders associated with BK channel mutations. These results demonstrate the unique mechanisms of BK channel activation and that these mechanisms are important factors in linking BK channel mutations to neurological disorders.

scholarly journals Selective inhibition of phosphodiesterase 1 relaxes urinary bladder smooth muscle: role for ryanodine receptor-mediated BK channel activation

2012 ◽  
Vol 303 (10) ◽  
pp. C1079-C1089 ◽  
Author(s):  
Wenkuan Xin ◽  
Rupal P. Soder ◽  
Qiuping Cheng ◽  
Eric S. Rovner ◽  
Georgi V. Petkov
Keyword(s):  
Membrane Potential ◽  
Guinea Pig ◽  
Muscle Force ◽  
Selective Inhibition ◽  
Bk Channels ◽  
Bk Channel ◽  
Channel Activation ◽  
Contraction Amplitude ◽  
Intracellular Ca ◽  
Camp Levels

The large conductance voltage- and Ca2+-activated K+ (BK) channel is a major regulator of detrusor smooth muscle (DSM) excitability and contractility. Recently, we showed that nonselective phosphodiesterase (PDE) inhibition reduces guinea pig DSM excitability and contractility by increasing BK channel activity. Here, we investigated how DSM excitability and contractility changes upon selective inhibition of PDE type 1 (PDE1) and the underlying cellular mechanism involving ryanodine receptors (RyRs) and BK channels. PDE1 inhibition with 8-methoxymethyl-3-isobutyl-1-methylxanthine (8MM-IBMX; 10 μM) increased the cAMP levels in guinea pig DSM cells. Patch-clamp experiments on freshly isolated DSM cells showed that 8MM-IBMX increased transient BK currents and the spontaneous transient hyperpolarization (STH) frequency by ∼2.5- and ∼1.8-fold, respectively. 8MM-IBMX hyperpolarized guinea pig and human DSM cell membrane potential and significantly decreased the intracellular Ca2+ levels in guinea pig DSM cells. Blocking BK channels with 1 μM paxilline or inhibiting RyRs with 30 μM ryanodine abolished the STHs and the 8MM-IBMX inhibitory effects on the DSM cell membrane potential. Isometric DSM tension recordings showed that 8MM-IBMX significantly reduced the spontaneous phasic contraction amplitude, muscle force integral, duration, frequency, and tone of DSM isolated strips. The electrical field stimulation-induced DSM contraction amplitude, muscle force integral, and duration were also attenuated by 10 μM 8MM-IBMX. Blocking BK channels with paxilline abolished the 8MM-IBMX effects on DSM contractions. Our data provide evidence that PDE1 inhibition relaxes DSM by raising cellular cAMP levels and subsequently stimulates RyRs, which leads to BK channel activation, membrane potential hyperpolarization, and decrease in intracellular Ca2+ levels.

First person – Fanny Jaudon and Martina Albini

2021 ◽  
Vol 134 (16) ◽  
Keyword(s):  
Neurotrophic Factor ◽  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Early Career ◽  
First Person ◽  
Early Career Researchers ◽  
And Function ◽  
The University ◽  
Selection Of

ABSTRACT First Person is a series of interviews with the first authors of a selection of papers published in Journal of Cell Science, helping early-career researchers promote themselves alongside their papers. Fanny Jaudon and Martina Albini are co-first authors on ‘ A developmental stage- and Kidins220-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor’, published in JCS. Fanny is a postdoc at the University of Trieste in the lab of Lorenzo A. Cingolani at Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genova, Italy, investigating the molecular mechanisms controlling development and function of neuronal circuits and implementing genome-editing approaches for the treatment of neurological disorders. Martina is a PhD student at the Istituto Italiano di Tecnologia in the lab of Fabio Benfenati and Fabrizia Cesca investigating neurotrophin biology and its involvement in neurological diseases.

scholarly journals Role of Enzymes in Causing Neurological Disorders

2021 ◽  
Vol 12 (1) ◽  
pp. 466-476
Author(s):  
Vysakh Visweswaran ◽  
Roshni PR
Keyword(s):  
Neurological Disorders ◽  
Drug Targets ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Treatment Options ◽  
Direct Result ◽  
Permanent Disability ◽  
Genetic Abnormalities ◽  
Underlying Pathology

Diseases of the nervous system are always associated with poor prognosis and limited treatment options. The fragile nature of the neurons and their inability to replicate means that neurological disorders are associated with a permanent disability. Pharmacotherapy of neurological diseases requires understanding the molecular mechanisms involved in the disease pathology. In most of the cases a faulty cellular biochemical pathway is involved, resulting from a defective enzyme. This article focusses on role of enzymes in various neurological disorders. To review pertinent literature and summarise the role of enzymes in the underlying pathology of various neurological disorders. A comprehensive literature search was conducted using PubMed, SCOPUS, J-GATE and Google Scholar and relevant papers were collected using the keywords enzymes, Alzheimer's disease, redox, thiamine, depression, neurotransmitters, epileptogenesis. The literature review highlighted the role of enzymes in major neurological disorders and their potential to be used as drug targets and biomarkers. Identifying defective enzymes gives us new molecular targets to focus on for developing more effective pharmacotherapeutic options. They can be also considered as potential biomarkers. An abnormal enzyme is most often a direct result of an underlying genetic abnormality. Identifying and screening for these genetic abnormalities can be used in early identification and prevention of disease in individuals who have a genetic predisposition. The modern advances in genetic engineering shows a lot of promise in correcting these abnormalities and development of revolutionary cures although ethical concerns remain. 

scholarly journals Much More Than a Scaffold: Cytoskeletal Proteins in Neurological Disorders

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 358 ◽  
Author(s):  
Diana C. Muñoz-Lasso ◽  
Carlos Romá-Mateo ◽  
Federico V. Pallardó ◽  
Pilar Gonzalez-Cabo
Keyword(s):  
Neurological Disorders ◽  
Actin Filaments ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Three Dimensional ◽  
Cytoskeletal Proteins ◽  
Dimensional Lattice ◽  
New Treatments ◽  
And Function

Recent observations related to the structure of the cytoskeleton in neurons and novel cytoskeletal abnormalities involved in the pathophysiology of some neurological diseases are changing our view on the function of the cytoskeletal proteins in the nervous system. These efforts allow a better understanding of the molecular mechanisms underlying neurological diseases and allow us to see beyond our current knowledge for the development of new treatments. The neuronal cytoskeleton can be described as an organelle formed by the three-dimensional lattice of the three main families of filaments: actin filaments, microtubules, and neurofilaments. This organelle organizes well-defined structures within neurons (cell bodies and axons), which allow their proper development and function through life. Here, we will provide an overview of both the basic and novel concepts related to those cytoskeletal proteins, which are emerging as potential targets in the study of the pathophysiological mechanisms underlying neurological disorders.

scholarly journals BK Channels in Rat and Human Pulmonary Smooth Muscle Cells are BKα-β1 Functional Complexes Lacking the Oxygen-Sensitive Stress Axis Regulated Exon Insert

2016 ◽  
Vol 6 (4) ◽  
pp. 563-575 ◽  
Author(s):  
Neil D. Detweiler ◽  
Li Song ◽  
Samantha J. McClenahan ◽  
Rachel J. Versluis ◽  
Sujay V. Kharade ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Splice Variants ◽  
Muscle Cells ◽  
Bk Channels ◽  
Bk Channel ◽  
Stress Axis ◽  
Human Donor ◽  
Intracellular Ca ◽  
Oxygen Sensitive

A loss of K+ efflux in pulmonary arterial smooth muscle cells (PASMCs) contributes to abnormal vasoconstriction and PASMC proliferation during pulmonary hypertension (PH). Activation of high-conductance Ca2+-activated (BK) channels represents a therapeutic strategy to restore K+ efflux to the affected PASMCs. However, the properties of BK channels in PASMCs—including sensitivity to BK channel openers (BKCOs)—are poorly defined. The goal of this study was to compare the properties of BK channels between PASMCs of normoxic (N) and chronic hypoxic (CH) rats and then explore key findings in human PASMCs. Polymerase chain reaction results revealed that 94.3% of transcripts encoding BKα pore proteins in PASMCs from N rats represent splice variants lacking the stress axis regulated exon insert, which confers oxygen sensitivity. Subsequent patch-clamp recordings from inside-out (I-O) patches confirmed a dense population of BK channels insensitive to hypoxia. The BK channels were highly activated by intracellular Ca2+ and the BKCO lithocholate; these responses require BK α-β1 subunit coupling. PASMCs of CH rats with established PH exhibited a profound overabundance of the dominant oxygen-insensitive BKα variant. Importantly, human BK (hBK) channels in PASMCs from human donor lungs also represented the oxygen-insensitive BKα variant activated by BKCOs. The hBK channels showed significantly enhanced Ca2+ sensitivity compared with rat BK channels. We conclude that rat BK and hBK channels in PASMCs are oxygen-insensitive BK α-β1 complexes highly sensitive to Ca2+ and the BKCO lithocholate. BK channels are overexpressed in PASMCs of a rat model of PH and may provide an abundant target for BKCOs designed to restore K+ efflux.

scholarly journals Transduction of Voltage and Ca2+ Signals by Slo1 BK Channels

Physiology ◽  
2013 ◽  
Vol 28 (3) ◽  
pp. 172-189 ◽  
Author(s):  
T. Hoshi ◽  
A. Pantazis ◽  
R. Olcese
Keyword(s):  
Gate Voltage ◽  
Bk Channels ◽  
Activation Mechanism ◽  
Channel Activation ◽  
Regulatory Factors ◽  
Voltage Sensors ◽  
Voltage Gated ◽  
Intracellular Ca ◽  
Biophysical Mechanism ◽  
Allosteric Model

Large-conductance Ca2+- and voltage-gated K+ channels are activated by an increase in intracellular Ca2+ concentration and/or depolarization. The channel activation mechanism is well described by an allosteric model encompassing the gate, voltage sensors, and Ca2+ sensors, and the model is an excellent framework to understand the influences of auxiliary β and γ subunits and regulatory factors such as Mg2+. Recent advances permit elucidation of structural correlates of the biophysical mechanism.

scholarly journals Molecular mechanism of BK channel activation by the smooth muscle relaxant NS11021

2020 ◽  
Vol 152 (6) ◽  
Author(s):  
Michael E. Rockman ◽  
Alexandre G. Vouga ◽  
Brad S. Rothberg
Keyword(s):  
Smooth Muscle ◽  
Muscle Relaxant ◽  
Time Course ◽  
Bk Channels ◽  
Bk Channel ◽  
Neurological Deficits ◽  
Open Probability ◽  
Channel Activation ◽  
Voltage Sensors ◽  
Smooth Muscle Relaxant

Large-conductance Ca2+-activated K+ channels (BK channels) are activated by cytosolic calcium and depolarized membrane potential under physiological conditions. Thus, these channels control electrical excitability in neurons and smooth muscle by gating K+ efflux and hyperpolarizing the membrane in response to Ca2+ signaling. Altered BK channel function has been linked to epilepsy, dyskinesia, and other neurological deficits in humans, making these channels a key target for drug therapies. To gain insight into mechanisms underlying pharmacological modulation of BK channel gating, here we studied mechanisms underlying activation of BK channels by the biarylthiourea derivative, NS11021, which acts as a smooth muscle relaxant. We observe that increasing NS11021 shifts the half-maximal activation voltage for BK channels toward more hyperpolarized voltages, in both the presence and nominal absence of Ca2+, suggesting that NS11021 facilitates BK channel activation primarily by a mechanism that is distinct from Ca2+ activation. 30 µM NS11021 slows the time course of BK channel deactivation at −200 mV by ∼10-fold compared with 0 µM NS11021, while having little effect on the time course of activation. This action is most pronounced at negative voltages, at which the BK channel voltage sensors are at rest. Single-channel kinetic analysis further shows that 30 µM NS11021 increases open probability by 62-fold and increases mean open time from 0.15 to 0.52 ms in the nominal absence of Ca2+ at voltages less than −60 mV, conditions in which BK voltage sensors are largely in the resting state. We could therefore account for the major activating effects of NS11021 by a scheme in which the drug primarily shifts the pore-gate equilibrium toward the open state.

scholarly journals Spontaneous Transient Outward Currents Arise from Microdomains Where BK Channels Are Exposed to a Mean Ca2+ Concentration on the Order of 10 μM during a Ca2+ Spark

2002 ◽  
Vol 120 (1) ◽  
pp. 15-27 ◽  
Author(s):  
Ronghua ZhuGe ◽  
Kevin E. Fogarty ◽  
Richard A. Tuft ◽  
John V. Walsh
Keyword(s):  
Voltage Dependence ◽  
Ryanodine Receptors ◽  
Bk Channels ◽  
Bk Channel ◽  
Channel Activation ◽  
Membrane Area ◽  
Outward Currents ◽  
Cell Recording ◽  
Excised Patches ◽  
Spontaneous Transient Outward Currents

Ca2+ sparks are small, localized cytosolic Ca2+ transients due to Ca2+ release from sarcoplasmic reticulum through ryanodine receptors. In smooth muscle, Ca2+ sparks activate large conductance Ca2+-activated K+ channels (BK channels) in the spark microdomain, thus generating spontaneous transient outward currents (STOCs). The purpose of the present study is to determine experimentally the level of Ca2+ to which the BK channels are exposed during a spark. Using tight seal, whole-cell recording, we have analyzed the voltage-dependence of the STOC conductance (g(STOC)), and compared it to the voltage-dependence of BK channel activation in excised patches in the presence of different [Ca2+]s. The Ca2+ sparks did not change in amplitude over the range of potentials of interest. In contrast, the magnitude of g(STOC) remained roughly constant from 20 to −40 mV and then declined steeply at more negative potentials. From this and the voltage dependence of BK channel activation, we conclude that the BK channels underlying STOCs are exposed to a mean [Ca2+] on the order of 10 μM during a Ca2+ spark. The membrane area over which a concentration ≥10 μM is reached has an estimated radius of 150–300 nm, corresponding to an area which is a fraction of one square micron. Moreover, given the constraints imposed by the estimated channel density and the Ca2+ current during a spark, the BK channels do not appear to be uniformly distributed over the membrane but instead are found at higher density at the spark site.

scholarly journals Effects of Neurological Disorders on Bone Health

2020 ◽  
Vol 11 ◽  
Author(s):  
Ryan R. Kelly ◽  
Sara J. Sidles ◽  
Amanda C. LaRue
Keyword(s):  
Bone Health ◽  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Neurological Diseases ◽  
Sensory Innervation ◽  
Current Evidence ◽  
Bone Homeostasis ◽  
Shared Risk ◽  
The Brain

Neurological diseases, particularly in the context of aging, have serious impacts on quality of life and can negatively affect bone health. The brain-bone axis is critically important for skeletal metabolism, sensory innervation, and endocrine cross-talk between these organs. This review discusses current evidence for the cellular and molecular mechanisms by which various neurological disease categories, including autoimmune, developmental, dementia-related, movement, neuromuscular, stroke, trauma, and psychological, impart changes in bone homeostasis and mass, as well as fracture risk. Likewise, how bone may affect neurological function is discussed. Gaining a better understanding of brain-bone interactions, particularly in patients with underlying neurological disorders, may lead to development of novel therapies and discovery of shared risk factors, as well as highlight the need for broad, whole-health clinical approaches toward treatment.

scholarly journals Molecular mechanisms of BK channel activation

2008 ◽  
Vol 66 (5) ◽  
pp. 852-875 ◽  
Author(s):  
J. Cui ◽  
H. Yang ◽  
U. S. Lee
Keyword(s):  
Molecular Mechanisms ◽  
Bk Channel ◽  
Channel Activation
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