Channelpedia

BKβ

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Introduction

BK channels exist in vivo as a complex of a tetramer of alfa-subunit (125 kDa) and a beta-subunit (31 kDa glycosylated regulatory protein).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:

BK channels present different sensitivity to calcium depending on the tissues, due to coassembly with the four different auxiliary beta-subunits.

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Structure

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]:

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

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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.

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Expression and Distribution

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].

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CNS Sub-cellular Distribution

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]

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Function

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]

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Interaction

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].

References

540

Orio P et al. New disguises for an old channel: MaxiK channel beta-subunits.
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557

MacKinnon R et al. Functional stoichiometry of Shaker potassium channel inactivation.
Science, 1993 Oct 29 , 262 (757-9).

558

Yuan P et al. Structure of the human BK channel Ca2+-activation apparatus at 3.0 A resolution.
Science, 2010 Jul 9 , 329 (182-6).

563

Yusifov T et al. The RCK2 domain of the human BKCa channel is a calcium sensor.
Proc. Natl. Acad. Sci. U.S.A., 2008 Jan 8 , 105 (376-81).

564

Schreiber M et al. A novel calcium-sensing domain in the BK channel.
Biophys. J., 1997 Sep , 73 (1355-63).

565

Gribkoff VK et al. Voltage-gated cation channel modulators for the treatment of stroke.
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568

Hou S et al. The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels.
Proc. Natl. Acad. Sci. U.S.A., 2008 Mar 11 , 105 (4039-43).

1100

Vergara C et al. Calcium-activated potassium channels.
Curr. Opin. Neurobiol., 1998 Jun , 8 (321-9).

1156

Adelman JP et al. Calcium-activated potassium channels expressed from cloned complementary DNAs.
Neuron, 1992 Aug , 9 (209-16).

1158

Wei A et al. Calcium sensitivity of BK-type KCa channels determined by a separable domain.
Neuron, 1994 Sep , 13 (671-81).

1169

Brenner R et al. Vasoregulation by the beta1 subunit of the calcium-activated potassium channel.
Nature, 2000 Oct 19 , 407 (870-6).

1172

Kaczorowski GJ et al. High-conductance calcium-activated potassium channels; structure, pharmacology, and function.
J. Bioenerg. Biomembr., 1996 Jun , 28 (255-67).

1180

Wallner M et al. Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane beta-subunit homolog.
Proc. Natl. Acad. Sci. U.S.A., 1999 Mar 30 , 96 (4137-42).

1216

Nardi A et al. BK channel modulators: a comprehensive overview.
Curr. Med. Chem., 2008 , 15 (1126-46).

1217

O'Rourke B et al. Mitochondrial ion channels: gatekeepers of life and death.
, 2005 Oct , 20 (303-15).

1218

Kang SH et al. Mitochondrial Ca2+-activated K+ channels more efficiently reduce mitochondrial Ca2+ overload in rat ventricular myocytes.
Am. J. Physiol. Heart Circ. Physiol., 2007 Jul , 293 (H307-13).

1454

Kuiper EF et al. K(Ca)2 and k(ca)3 channels in learning and memory processes, and neurodegeneration.
Front Pharmacol, 2012 , 3 (107).

1455

Widmer HA et al. Conditional protein phosphorylation regulates BK channel activity in rat cerebellar Purkinje neurons.
J. Physiol. (Lond.), 2003 Oct 15 , 552 (379-91).

1457

Berkefeld H et al. Ca2+-activated k+ channels: from protein complexes to function.
Physiol. Rev., 2010 Oct , 90 (1437-59).

1459

Wulff H et al. K+ channel modulators for the treatment of neurological disorders and autoimmune diseases.
Chem. Rev., 2008 May , 108 (1744-73).

1463

Sørensen MV et al. Aldosterone increases KCa1.1 (BK) channel-mediated colonic K+ secretion.
J. Physiol. (Lond.), 2008 Sep 1 , 586 (4251-64).

1465

Siemen D et al. Ca2+-activated K channel of the BK-type in the inner mitochondrial membrane of a human glioma cell line.
Biochem. Biophys. Res. Commun., 1999 Apr 13 , 257 (549-54).

1467

Khan RN et al. Potassium channels in the human myometrium.
Exp. Physiol., 2001 Mar , 86 (255-64).

1469

Church J et al. pH modulation of Ca2+ responses and a Ca2+-dependent K+ channel in cultured rat hippocampal neurones.
J. Physiol. (Lond.), 1998 Aug 15 , 511 ( Pt 1) (119-32).

1472

Raffaelli G et al. BK potassium channels control transmitter release at CA3-CA3 synapses in the rat hippocampus.
J. Physiol. (Lond.), 2004 May 15 , 557 (147-57).

1475

Werner ME et al. Erectile dysfunction in mice lacking the large-conductance calcium-activated potassium (BK) channel.
J. Physiol. (Lond.), 2005 Sep 1 , 567 (545-56).

1476

Meredith AL et al. Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel.
J. Biol. Chem., 2004 Aug 27 , 279 (36746-52).

1477

Rüttiger L et al. Deletion of the Ca2+-activated potassium (BK) alpha-subunit but not the BKbeta1-subunit leads to progressive hearing loss.
Proc. Natl. Acad. Sci. U.S.A., 2004 Aug 31 , 101 (12922-7).

1478

Sausbier M et al. Cerebellar ataxia and Purkinje cell dysfunction caused by Ca2+-activated K+ channel deficiency.
Proc. Natl. Acad. Sci. U.S.A., 2004 Jun 22 , 101 (9474-8).

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