China
Africa
Explore chapters and articles related to this topic
Restoration of Membrane Environments for Membrane Proteins for Structural and Functional Studies
Published in Qiu-Xing Jiang, New Techniques for Studying Biomembranes, 2020
The BK channel is a member of the Slo family, whose α-subunits contain regulator-of-conductance-for-K+ (RCK) domains in their large intracellular C-terminal region. In all determined structures made of RCK domains [49–56], a four-fold symmetry along the central pore (C4) was observed. With the restoration of the lipid membrane of the BK channel, a two-fold symmetry (C2) was observed in the 3.5-Å EM density map of the BK channel [20]. This is an intermediate state of the BK channel and has not been accessible by other methods (e.g., x-ray crystallography, cryo-EM of detergent solubilized membrane proteins). This two-fold symmetry in a homotetramer channel was also observed in the recently determined structure of a voltage-gated sodium channel (the human Nav1.7 channel) [57]. Thus, it is critical to reconstitute membrane proteins into liposomes in order to probe more physiologically relevant functional states of membrane proteins.
Pathophysiology of neurogenic detrusor overactivity
Published in Jacques Corcos, David Ginsberg, Gilles Karsenty, Textbook of the Neurogenic Bladder, 2015
Alexandra McPencow, Toby C. Chai
The large conductance of calcium-activated potassium channel (BK) has been shown to be important regulator of normal human and mouse DSM contractility.44,45 When BK is open (activated by increased intracellular calcium and/or cellular depolarization), potassium flows out of the cell, thus hyperpolarizing the cell and reducing the ability of the cell to contract and/or generate spontaneous activity. The depiction of BK morphology is shown in Figure 7.5. Each BK channel is composed of 4 units (tetramer) of BK protein. Each BK protein unit has an α-subunit (pore-forming unit) and a β-subunit (regulatory unit). Each α-subunit has seven transmembrane domains, whereas each β-subunit has two transmembrane domains. Alternative splicing of the BK gene (KCNMA1) can further regulate the properties of the BK channel.
Physiological Properties of the Lower Urinary Tract
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
The most significant K+ channel in detrusor is the Ca2+-activated large conductance K+ channel (BKCa). This channel has physiological roles in determining membrane potential, AP repolarization (176), and regulating contractile events (70): channel opening is coupled to intracellular Ca2+ sparks emanating from intracellular Ca stores via ryanodine receptors (176). Outward current is also modulated by Ca2+ current influx through L-type and T-type Ca2+ channels. In the former case this has been proposed as a mechanism to regulate Ca2+ influx into the myocyte (70), and in the latter case as a basis for spontaneous fluctuations of membrane potential (177). Reduction in BK channel activity may contribute to myogenic bladder overactivity, as deletion of the slo-gene that encodes for the channel protein enhances muscle sensitivity to cholinergic and purinergic agonists (178); conversely injection of slo-cDNA reduced overactivity (179). BK channel activity is regulated by phosphorylation of the pore-forming a-subunit, or associated proteins (180), and affords a mechanism whereby cAMP and cGMP, through PKC, can regulate channel function. Conversely, the Ca2+-dependent phosphatase, calcineurin, decreased BKCa conductance (181) so that overall Ca2+ exerts a complex control of channel function.
Clinical direction in the pharmacological and device management of refractory overactive bladder: the urge to develop new treatments
Published in Expert Opinion on Pharmacotherapy, 2022
A recently developed therapy in trials for those who have failed first- and second-line treatment options includes gene therapy. URO-902 is a plasmid DNA (pDNA) vector that expresses the α subunit of the human big potassium (BK) channel, a large-conductance Ca2+-activated K+ channel that creates and maintains the cell’s resting membrane potential. The BK channel is normally expressed at high levels in detrusor smooth muscle and functions in bladder smooth muscle to control spontaneous amplitude and duration of detrusor contraction while promoting detrusor relaxation. Reduced BK channel expression is associated with neurogenic detrusor overactivity leading to increased detrusor smooth muscle contractility and excitability [14]. Injection of URO-902 into the detrusor muscle is believed to increase the number of BK channels thereby improving bladder hypercontractility. Because URO-902 uses naked pDNA, it may confer lower immunogenic risk when compared with viral or retroviral vectors [14].
Potassium channels as prominent targets and tools for the treatment of epilepsy
Published in Expert Opinion on Therapeutic Targets, 2021
Among calcium-gated potassium channels that play an important role in opposing repetitive firing and hyperexcitability typical of epilepsy, mostly BK and KCa4.1 (Slack) channel mutations have been reported in patients with epilepsy [88]. Gain- and loss-of-function mutations of BK channel subunits were found in epilepsy with and without paroxysmal dyskinesia [89–91]. Gain-of-function mutations were proposed to increase neuronal excitability by allowing rapid repolarization of action potentials and faster firing. Pathogenic variants of sodium-activated potassium channels (KCa4.1) have been implicated in epilepsy in infancy with migrating focal seizures, autosomal-dominant nocturnal frontal lobe epilepsy [92–97], Ohtahara syndrome [98] and other types of early onset epileptic encephalopathies [99,100]. Mutations of KCa4.2 channel subunits were also reported in patients with developmental and epileptic encephalopathies and West syndrome, followed by Lennox-Gastaut syndrome [101–103].
The role of lysosomal ion channels in lysosome dysfunction
Published in Inhalation Toxicology, 2021
Rebekah L. Kendall, Andrij Holian
The Ca2+-activated big-conductance K+ (BK) channel is composed of four pore-forming BK α-subunits each with 7 transmembrane segments and an extracellular N-terminus. BK channels are characterized by a large K+ conductance that can be activated by membrane depolarization or elevated cytosolic Ca2+. BK channels are ubiquitously expressed on the plasma membrane of excitable cells where their activation results in an efflux of K + from the cytosol, causing hyperpolarization of the membrane and regulating membrane excitability (Yang et al. 2015). Though present in much smaller numbers on the lysosomal membrane than the plasma membrane, lysosomal BK channels have such a high conductance that their activity is sufficient to produce significant changes in lysosomal membrane potential (Wang et al. 2017a), facilitating the movement of K+ ions from the cytosol (into the lysosomal lumen) and causing hyperpolarization of the lysosomal membrane (Cao et al. 2015). BK channel activity is tightly coupled to TRPML1 Ca2+ release. Activation of the BK channel by TRPML1 Ca2+ release allows BK channels to provide a counter cation flux across the lysosomal membrane and maintain the membrane potential necessary for continued TRMPL1 and V-ATPase activity (Cao et al. 2015).