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BK


Synonyms: . Symbol:

Introductions


KCa1.1 (also called Slo, Slo1, and BK or maxi K channel are ion channels characterized by their large conductance of potassium ions (K+) through cell membranes (260 pS). BK channel forms tetrameric complexes composed of four ion-conducting α subunits, each with 7 transmembrane segments and an intracellular domain which acts as Ca2+ sensor, and four regulatory β subunits (four variants of which exist). [1458]
These channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellular calcium ion (Ca2+).[558][556]. Under typical physiological conditions, this results in an efflux of K+ from the cell, which leads to cell membrane hyperpolarization (a decrease in the electrical potential across the cell membrane) and a decrease in cell excitability (a decrease in the probability that the cell will transmit an action potential). It is expressed by a wide variety of cells, including neurons and myocytes, and has pleiotropic functions. It can respond to transient Ca2+ increases (“sparks”) originated by opening of Ca2+ channels or sarcoplasmic reticulum ryanodine receptors, and it has been observed to form clusters optimally positioned for such local responses, for which it seems to have been particularly designed by evolution since it responds to [Ca2+] in the µM range. [1458].

Genes


:

RGD ID Chromosome Position Species
2961 10 18904902-18912604 Rat
736975 11 33863013-33873638 Mouse
733456 5 169805167-169816638 Human

Transcripts


Acc No Sequence Length Source
NM_019273 NCBI
NM_031169 NCBI
NM_004137 NCBI

Ontologies


Accession Name Definition Evidence
GO:0008076 voltage-gated potassium channel complex A protein complex that forms a transmembrane channel through which potassium ions may cross a cell membrane in response to changes in membrane potential. IEA
GO:0016020 membrane Double layer of lipid molecules that encloses all cells, and, in eukaryotes, many organelles; may be a single or double lipid bilayer; also includes associated proteins. IEA
GO:0016021 integral to membrane Penetrating at least one phospholipid bilayer of a membrane. May also refer to the state of being buried in the bilayer with no exposure outside the bilayer. When used to describe a protein, indicates that all or part of the peptide sequence is embedded in the membrane. IEA

Interactions


BK channels are activated by voltage and intracellular Ca2+ and Mg2+. The BK channel contains the transmembrane voltage sensitive domain as well as Ca2+ and Mg2+ binding. The voltage and metal sensors all control the opening of the same ionic pore in response to various physiological signals [1460]. There is evidence of changes in BK channel activity by phosphorylation and/or interaction by G proteins, by mechanical stretch, and by various endothelium-derived vasoactive substances [540].

In contrast to the relatively small number of BK inhibitors, a large number of both natural and synthetic BK activators have been reported (see Figure 6 Wulff and Zhorov 2008 [1459]).

Some of the molecules and substances that interact with BK channels:

Calmodulin
Calmodulin (CaM) is constitutively bound to the C terminus of the channel and binds calcium leading to a conformational change enabling opening of the cannel and potassium efflux. [1454] [1158]

Kinases
The protein has multiple predicted phosphorylation sites that can modulate channel function by phosphorylation [1454]. The activation of protein kinase C completely suppresses the opening BK channels in intact rat anterior pituitary cells in physiological saline. In fact, in rat cerebellar Purkinje neurons there are multiple endogenous protein kinases and phosphatases that functionally couple to the BK channel modulating their activity. Moreover, each type of neuronal BK channels are differentially sensitive to PKA-dependent phosphorylation. [1455]

Adrenal glucocorticoids Adrenal glucocorticoids regulate adaptation mechanisms to environmental challenges ([1461]) and can modify the electrical excitability of BK channels in human embryonic kidney cells. [1462]

Aldosterone
Aldosterone-induced K(+) secretion occurs via increased expression of luminal BK channels [1463].

Leptin
Leptin activates BK channels via PI 3-kinase controlling neuronal excitability. As uncontrolled excitability in the hippocampus is one underlying cause of temporal lobe epilepsy, leptin could be considered as therapeutic target. [1464]

Toxins
Mammalian BK channels are characterized by their high sensitivity to blockade by iberiotoxin (IbTx) and charybdotoxin. [1164]

Drugs
BMS-204352 (BMS) was developed as a neuroprotective drug for disease conditions such as ischemic stroke and it has been shown to have a protective effect, due to activation of big-conductance calcium-activating potassium (BKCa) channels (Gribkoff et al., 2001 [1214]; Cheney et al., 2001 [1215]; Nardi and Olesen, 2008 [1216]).

BK channels are pharmacological targets for the treatment of stroke. Various pharmaceutical companies developed synthetic molecules activating these channels [565] in order to prevent excessive neurotoxic calcium entry in neurons [566]. But BMS-204352 (MaxiPost) a molecule developed by Bristol-Myers Squibb failed to improve clinical outcome in stroke patients compared to placebo [571]. BK channels have also been found to be activated by exogenous pollutants and endogenous gazotransmitters carbon monoxide [568], [567] and hydrogen sulphide [569].

BK channels are blocked by tetraethylammonium (TEA), paxilline (http://www.fermentek.co.il/paxilline.htm) and iberiotoxin [570].

Proteins


Structures


As with other potassium channels, BK channels have a tetrameric structure. Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene. Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrametic channel.

K+ channels are formed as tetramers [557] of identical or similar subunits arranged in fourfold symmetry around the water-filled ion-conduction pathway (except for the 2P tandem channels, which are presumably dimers.) Common to all K+ channel subunits is a structural core consisting of two transmembrane helices, readily identified by hydrophobicity algorithms, separated by a re-entrant pore-loop carrying the signature sequence (Figure 1 in [556]).BK channels comprise seven transmembrane domains (S0-S6) placing the short NH2 terminus extracellularly and the COOH terminus (two-thirds of the protein) at the intracelular side of the membrane (see Figure 1 fo Berkefeld et al. 2010 [1457]). This intracelular domain contains four hydrophobic segments (S7- S10), two regulating conductance of potassium (RCK domains) and a stretch of aspartate residues that are known as the “Calcium bowl”. Calcium binding and membrane depolarization, converge allosterically on the gating the channel [1457]. The primary sequences among different mammalian BK channels are almost identical, and share a high degree of homology with the sequences of the six transmembrane segments Sl-S6 of the superfamily of voltage-gated potassium (K,) channels. The homology among positively charged amino acids in the S4 segment that forms part of the voltage sensor in K. [1100]

BK channels are a prime example of modular protein evolution. Each BK channel alpha subunit consists of (from N- to C-terminal):

  1. A unique transmembrane domain (S0)[560] that precedes the 6 transmembrane domains (S1-S6) conserved in all voltage-dependent K+ channels.
  2. A voltage sensing domain (S1-S4).
  3. A K+ channel pore domain (S5, selectivity filter, and S6).
  4. A cytoplasmic C-terminal domain (CTD) consisting of a pair of RCK domains that assemble into an octameric gating ring on the intracellular side of the tetrameric channel [558], [562], [561], [563], [564].

BK channels exist in vivo as a complex of the alfa-subunit (125 kDa) and a beta-subunit (31 kDa glycosylated regulatory protein). The minimal molecular component necessary and sufficient for BK activity is its pore-forming alfa-subunit, and functional channels are formed as tetramers of this protein. [540]. The functional diversity of BK channels are due ,in part, to various splice variants of the α subunit encoded by the Slo loci [1156] Accessory β subunits play an important role in defining the phenotypic properties of BK channels, including the effective gating range and inactivation behavior.
Four distinct members of a mammalian β subunit family have been identified each of which appears to confer unique functional properties on the resulting BK channels:
-KCNMB1 (β1) [1167]
-KCNMB2 (β2) [1180]
-KCNMB3 (β3) [1494] [1181]
-KCNMB4 (β4) [1181]

Coexpression of the beta-subunit with the pore-forming alfa-1 subunit affects the apparent calcium sensitivity, by eliciting a negative shift in the voltage range of activation. ([1163]), [1100]

Beta-subunits

Regulatory beta-subunits share a putative membrane topology: with two transmembrane segments connected by a 120- residue extracellular “loop” and with NH2 and COOH terminals oriented toward the cytoplasm. The loop has three or four putative glycosylation sites [540], [1459]:
-beta-1: increase the stability of the open state, modifies channel kinetics and alters its pharmacological properties. It is primarily expressed in smooth muscle, hair cells, and some neurons.
-beta2: coexpression of alfa- and beta2-subunits produces inactivating currents and is found in ovary and endrocrine tissue.
-beta3: was cloned from human EST databases. It was detected in testis, pancreas, and spleen and it is phylogenetically more related to beta2 than to beta1. There are four splice variants whose differences are in the NH2-terminal region and each one confers different inactivation properties.
-beta4: is expressed mainly in brain. Its coexpression with the alfa- subunit decreases the apparent Ca2+ sensitivity of the BK channel.

Physiological roles of BK beta-subunits: Figure 3 of Orio et al. 2004 [540].

Calcium-sensing domains: the calcium bowl

The region between S9 and S1O binds calcium and participate in activation and is termed “the calcium bowl’. This region contains many negatively charged residues, mostly aspartates, and is highly conserved among different species and is highly selective for calcium [564], [558], [561].

Available X-ray structures:

-3MT5 Crystal Structure of the Human BK Gating Apparatus [558]
-3NAF Structure of the Intracellular Gating Ring from the Human High-conductance Ca2+ gated K+ Channel (BK Channel) [561]

Distributions


In the brain, BK is found in the soma, dendrites, and presynaptic terminals of neurons and is thought to underlie the fast afterhyperpolarization current and to regulate synaptic transmission by limiting the Ca2+ influx through CaV channels [1459]. BK channels are described in mitochondrial membrane of several cells, such human glioma cells and ventricular cells in guinea pigs. [1465], [1466]

Expressions


BK channels are widely expressed throughout the body: both in brain (cerebellum, habenula, striatum, olfactory bulb, neocortex, granule and pyramidal cells of the hippocampus) and peripheral tissue (skeletal muscle, smooth muscle (vascular, uterine, gastric, bladder), adrenal cortex, cochlear hair cells, odontoblasts, pancreatic islet cells, colonic and kidney epithelium). [1459], [539].
BK is also expressed in human glioma [1465].

Functionals


BK channels are essential for the regulation of several key physiological processes including smooth muscle tone and neuronal excitability.(http://www.ncbi.nlm.nih.gov/gene/3778)

BK channels exhibit a very high single-channel conductance, are potassium selective and they are activated by the concerted influences of membrane depolarization and increases in calcium concentration. These characteristics explain their proposed role as feedback modulators of the activity of voltage-dependent calcium channels with whom they coexist in both neurons and smooth muscle cells. [1467]

BK channels present different sensitivity to calcium depending on the tissues and therefore, differential inactivation properties and pharmacology. These differences are due to alternative splicing of the alfa-subunit and coassembly with four different auxiliary beta-subunits. While beta-1 is primarily expressed in smooth muscle, hair cells, and some neurons, beta-2 is found in ovary and endocrine tissue, beta-3 in testis, and beta-4 is the most abundant beta-subunit in the brain [1459]. Moreover, the high ratio of β-subunit:α-subunit of BK channels in brain leads them higher calcium sensitivity in cerebral vasculature in comparison with skeletal muscle [1468]. Specifically, the beta1 subunit influence on calcium sensitivity and has a key role on vasoregulation [1169]. Changes in intracellular pH also affect the unitary properties of BK channels [1469].

BK channels are implicated in distinct physiological functions related to the tissue where they are expressed:
-BK channels regulate electrical activity in β-cells of mouse pancreatic islets exposed to elevated glucose [1470].
-These channels activity underlie neuroadaptation to alcohol and neuronal plasticity [1471].BK channels also contribute to the behavioral effects of ethanol in the worm C. elegans under high concentrations (> 100 mM, or approximately 0.50% BAC).[559]
-BK potassium channels regulate neuronal firing and control transmitter release and synaptic efficacy at CA3-CA3 synapses in the rat hippocampus. [1472]
-In cardiac myocytes, BKCa channel activators can be used as specific activators for mitochondrial BKCa channels because they are only expressed in the mitochondrial membrane and not in the cell membrane, which may be pivotal in the cardioprotective effect in cardiac myocytes [1217]; Kang et al., 2007 [1218]).

Channels activators may have applications in several physiological alterations such stroke, epilepsy, bladder over-reactivity, asthma, hypertension, gastric hypermotility and psychoses. [539], [1214], [1172], [1474].

Mouse models:
* Slo-/- , erectil dysfunction [1475] and overactive bladder and incontinence [1476]
* BKbeta1-/- (hearing loss) [1477]
* BK-/- (cerebellar ataxia) [1478]

Kinetics


BK channels mediate fast afterhyperpolarization in neurones, electrical tuning of nonspiking properties of cochlear hair cells, presynaptic regulation of neurotransmitter release, effector of calcium sparks in smooth muscles [539].

BK channels differential function are related with their differential implication in physiological regulations [1457]:
Smooth muscle: BKs are activated by calcium sparks and/or by L-type Cav channels, promoting relaxation of the muscle cell.
•In the two types of chromaffin cells in adrenal glands, BK channels show distinct gating properties and show different firing patterns. The slowly deactivating BK-beta2/3 channels give rise to a pronounced afterhyperpolarization that relieves voltage-dependent sodium channels from inactivation and promotes repetitive or tonic firing. In contrast, the rapidly deactivating channels lead to only small afterhyperpolarizations that promote firing at a more phasic pattern.
•In CNS neurons, BK channels contribute to repolarization of action potentials (AP) and give rise to a fast afterhyperpolarization (fAHP) impacting on neuronal firing by “spike sharpening”. In hippocampal pyramidal cells, inactivating BK-beta2 channels promote frequency-dependent AP broadening along a spike train. In hippocampal granule cells, the slowed activation kinetics induced by coassembly with beta4 appears to operate as a “low-pass filter” that prevents high-frequency firing and spike sharpening.
•In auditory sensory hair cells of amphibians, birds, and fish, BK channels participate in “electrical ringing,” a resonance phenomenon fundamental for hearing. Basically, electrical ringing is depolarization-repolarization cycles that are generated by serial and repetitive activation of L-type Cav channels and BK channels. The frequency of these electrical oscillations is determined by the amplitude and kinetics of the BK currents and varies between hair cells along the axis of the hearing organ as a result of an expression gradient of the beta1.

Models


References


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[556 : 11178249]
[557 : 7694359]
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[565 : 15926865]
[566 : 11496927]
[567 : 15664403]
[568 : 18316727]
[569 : 19802723]
[570 : 1384740]
[571 : 12481191]
[1458 : 20036632]
[1163 : 9279807]
[1100 : 9687354]
[564 : 9284303]
[1460 : 20660558]
[540 : 12136044]
[1454 : 22701424]
[1455 : 14561822]
[1461 : 10696570]
[1462 : 11711561]
[1463 : 18617563]
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[1215 : 11323525]
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[1459 : 18476673]
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[1217 : 16174870]
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[1467 : 11429642]
[1468 : 23297302]
[1169 : 11057658]
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[1470 : 20643769]
[1471 : 18667155]
[1472 : 15034127]
[1214 : 11283675]
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[1474 : 11356099]
[1475 : 16020453]
[1476 : 15184377]
[1477 : 15328414]
[1478 : 15194823]
[539 : 16382103]
[1457 : 20959620]
[1158 : 7917297]
[1156 : 1497890]
[1167 : 8006036]
[1180 : 10097176]
[1494 : 10585773]
[1181 : 10692449]

Credits