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{beta} subunit-specific modulations of BK channel function by a mutation associated with epilepsy and dyskinesia.
Lee US
,
Cui J
.
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Large conductance Ca(2+)-activated K(+) (BK) channels modulate many physiological processes including neuronal excitability, synaptic transmission and regulation of myogenic tone. A gain-of-function (E/D) mutation in the pore-forming alpha subunit (Slo1) of the BK channel was recently identified and is linked to human neurological diseases of coexistent generalized epilepsy and paroxysmal dyskinesia. Here we performed macroscopic current recordings to examine the effects of the E/D mutation on the gating kinetics, and voltage and Ca(2+) dependence of the BK channel activation in the presence of four different beta subunits (beta1-4). These beta subunits are expressed in a tissue-specific pattern and modulate BK channel function differently, providing diversity and specificity for BK channels in various physiological processes. Our results show that in human (h) Slo1-only channels, the E/D mutation increased the rate of opening and decreased the rate of closing, allowing a greater number of channels to open at more negative potentials both in the presence and absence of Ca(2+) due to increased Ca(2+) affinity and enhanced activation compared with the wild-type channels. Even in the presence of beta subunits, the E/D mutation exhibited these changes with the exception of beta3b, where Ca(2+) sensitivity changed little. However, quantitative examination of these changes shows the diversity of each beta subunit and the differential modulation of these subunits by the E/D mutation. For example, in the presence of the beta1 subunit the E/D mutation increased Ca(2+) sensitivity less but enhanced channel activation in the absence of Ca(2+) more than in hSlo1-only channels, while in the presence of the beta2 subunit the E/D mutation also altered inactivation properties. These findings suggest that depending on the distribution of the various beta subunits in the brain, the E/D mutation can modulate BK channels differently to contribute to the pathophysiology of epilepsy and dyskinesia. Additionally, these results also have implications on physiological processes in tissues other than the brain where BK channels play an important role.
Adelman,
Calcium-activated potassium channels expressed from cloned complementary DNAs.
1992,
Pubmed
,
Xenbase
Atkinson,
A component of calcium-activated potassium channels encoded by the Drosophila slo locus.
1991,
Pubmed
Bao,
Gating and ionic currents reveal how the BKCa channel's Ca2+ sensitivity is enhanced by its beta1 subunit.
2005,
Pubmed
,
Xenbase
Behrens,
hKCNMB3 and hKCNMB4, cloning and characterization of two members of the large-conductance calcium-activated potassium channel beta subunit family.
2000,
Pubmed
Benzinger,
Direct observation of a preinactivated, open state in BK channels with beta2 subunits.
2006,
Pubmed
,
Xenbase
Brayden,
Regulation of arterial tone by activation of calcium-dependent potassium channels.
1992,
Pubmed
Brenner,
Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4.
2000,
Pubmed
Brenner,
Vasoregulation by the beta1 subunit of the calcium-activated potassium channel.
2000,
Pubmed
Brenner,
BK channel beta4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures.
2005,
Pubmed
Cox,
Allosteric gating of a large conductance Ca-activated K+ channel.
1997,
Pubmed
,
Xenbase
Cox,
Role of the beta1 subunit in large-conductance Ca(2+)-activated K(+) channel gating energetics. Mechanisms of enhanced Ca(2+) sensitivity.
2000,
Pubmed
,
Xenbase
Cui,
Molecular mechanisms of BK channel activation.
2009,
Pubmed
Cui,
Allosteric linkage between voltage and Ca(2+)-dependent activation of BK-type mslo1 K(+) channels.
2000,
Pubmed
Díez-Sampedro,
Mechanism of increased open probability by a mutation of the BK channel.
2006,
Pubmed
Ding,
Steady-state and closed-state inactivation properties of inactivating BK channels.
2002,
Pubmed
,
Xenbase
Du,
Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder.
2005,
Pubmed
,
Xenbase
Faber,
Calcium-activated potassium channels: multiple contributions to neuronal function.
2003,
Pubmed
Fernández-Fernández,
Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension.
2004,
Pubmed
Fettiplace,
Mechanisms of hair cell tuning.
1999,
Pubmed
Findlay,
High-conductance K+ channel in pancreatic islet cells can be activated and inactivated by internal calcium.
1985,
Pubmed
Gu,
BK potassium channels facilitate high-frequency firing and cause early spike frequency adaptation in rat CA1 hippocampal pyramidal cells.
2007,
Pubmed
Herrera,
Negative feedback regulation of nerve-mediated contractions by KCa channels in mouse urinary bladder smooth muscle.
2005,
Pubmed
Herrera,
Regulation of urinary bladder smooth muscle contractions by ryanodine receptors and BK and SK channels.
2000,
Pubmed
Horrigan,
Coupling between voltage sensor activation, Ca2+ binding and channel opening in large conductance (BK) potassium channels.
2002,
Pubmed
,
Xenbase
Hu,
Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release.
2001,
Pubmed
Knot,
Ryanodine receptors regulate arterial diameter and wall [Ca2+] in cerebral arteries of rat via Ca2+-dependent K+ channels.
1998,
Pubmed
Lancaster,
Properties of two calcium-activated hyperpolarizations in rat hippocampal neurones.
1987,
Pubmed
Ledoux,
Calcium-activated potassium channels and the regulation of vascular tone.
2006,
Pubmed
Lorenz,
Allelic association of a truncation mutation of the KCNMB3 gene with idiopathic generalized epilepsy.
2007,
Pubmed
Markwardt,
Gating of maxi K+ channels studied by Ca2+ concentration jumps in excised inside-out multi-channel patches (myocytes from guinea pig urinary bladder).
1992,
Pubmed
Meera,
A calcium switch for the functional coupling between alpha (hslo) and beta subunits (KV,Ca beta) of maxi K channels.
1996,
Pubmed
,
Xenbase
Meredith,
Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel.
2004,
Pubmed
Nimigean,
The beta subunit increases the Ca2+ sensitivity of large conductance Ca2+-activated potassium channels by retaining the gating in the bursting states.
1999,
Pubmed
Orio,
Differential effects of beta 1 and beta 2 subunits on BK channel activity.
2005,
Pubmed
,
Xenbase
Orio,
New disguises for an old channel: MaxiK channel beta-subunits.
2002,
Pubmed
Petersen,
Electrophysiology of the pancreas.
1987,
Pubmed
Petkov,
Beta1-subunit of the Ca2+-activated K+ channel regulates contractile activity of mouse urinary bladder smooth muscle.
2001,
Pubmed
Roberts,
Colocalization of ion channels involved in frequency selectivity and synaptic transmission at presynaptic active zones of hair cells.
1990,
Pubmed
Robitaille,
Presynaptic calcium signals and transmitter release are modulated by calcium-activated potassium channels.
1992,
Pubmed
Sailer,
Immunolocalization of BK channels in hippocampal pyramidal neurons.
2006,
Pubmed
Sausbier,
Ca2+ -activated K+ channels of the BK-type in the mouse brain.
2006,
Pubmed
Savaria,
Large conducting potassium channel reconstituted from airway smooth muscle.
1992,
Pubmed
Schreiber,
A novel calcium-sensing domain in the BK channel.
1997,
Pubmed
,
Xenbase
Semenov,
BK channel beta1-subunit regulation of calcium handling and constriction in tracheal smooth muscle.
2006,
Pubmed
Sentí,
Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk.
2005,
Pubmed
Solaro,
Inactivating and noninactivating Ca(2+)- and voltage-dependent K+ current in rat adrenal chromaffin cells.
1995,
Pubmed
Thorneloe,
Urodynamic properties and neurotransmitter dependence of urinary bladder contractility in the BK channel deletion model of overactive bladder.
2005,
Pubmed
Uebele,
Cloning and functional expression of two families of beta-subunits of the large conductance calcium-activated K+ channel.
2000,
Pubmed
Wallner,
Molecular basis of fast inactivation in voltage and Ca2+-activated K+ channels: a transmembrane beta-subunit homolog.
1999,
Pubmed
,
Xenbase
Wang,
An S6 mutation in BK channels reveals beta1 subunit effects on intrinsic and voltage-dependent gating.
2006,
Pubmed
Wang,
Consequences of the stoichiometry of Slo1 alpha and auxiliary beta subunits on functional properties of large-conductance Ca2+-activated K+ channels.
2002,
Pubmed
,
Xenbase
Xia,
Molecular basis for the inactivation of Ca2+- and voltage-dependent BK channels in adrenal chromaffin cells and rat insulinoma tumor cells.
1999,
Pubmed
,
Xenbase
Xia,
Inactivation of BK channels by the NH2 terminus of the beta2 auxiliary subunit: an essential role of a terminal peptide segment of three hydrophobic residues.
2003,
Pubmed
,
Xenbase
Xia,
Multiple regulatory sites in large-conductance calcium-activated potassium channels.
2002,
Pubmed
Yang,
Subunit-specific effect of the voltage sensor domain on Ca2+ sensitivity of BK channels.
2008,
Pubmed
,
Xenbase
