Ca<sup>2+</sup>-Activated K<sup>+</sup>Channels: From Protein Complexes to Function

Berkefeld, Henrike; Fakler, Bernd; Schulte, Uwe

doi:10.1152/physrev.00049.2009

Cited by 229 publications

(212 citation statements)

References 253 publications

(221 reference statements)

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“…Furthermore, the LTH fetal channels appear relatively dephosphorylated (Fig. 3A), which potentially provides the LTH fetal channels with a capacity of up to a 10-fold increase in Ca 2ϩ affinity (33), depending upon extent of PKA or PKG signaling pathway stimulation (5,32).…”

Section: Discussionmentioning

confidence: 99%

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

Xing

Lin

Thorington

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Tao X, Lin MT, Thorington GU, Wilson SM, Longo LD, Hessinger DA. Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle. Am J Physiol Heart Circ Physiol 308: H707-H722, 2015. First published January 16, 2015; doi:10.1152/ajpheart.00564.2014.-Acclimatization to high-altitude, long-term hypoxia (LTH) reportedly alters cerebral artery contraction-relaxation responses associated with changes in K ϩ channel activity. We hypothesized that to maintain oxygenation during LTH, basilar arteries (BA) in the ovine adult and near-term fetus would show increased large-conductance Ca 2ϩ activated potassium (BK) channel activity. We measured BK channel activity, expression, and cell surface distribution by use of patch-clamp electrophysiology, flow cytometry, and confocal microscopy, respectively, in myocytes from normoxic control and LTH adult and nearterm fetus BA. Electrophysiological data showed that BK channels in LTH myocytes exhibited 1) lowered Ca 2ϩ set points, 2) left-shifted activation voltages, and 3) longer dwell times. BK channels in LTH myocytes also appeared to be more dephosphorylated. These differences collectively make LTH BK channels more sensitive to activation. Studies using flow cytometry showed that the LTH fetus exhibited increased BK ␤1 subunit surface expression. In addition, in both fetal groups confocal microscopy revealed increased BK channel clustering and colocalization to myocyte lipid rafts. We conclude that increased BK channel activity in LTH BA occurred in association with increased channel affinity for Ca 2ϩ and left-shifted voltage activation. Increased cerebrovascular BK channel activity may be a mechanism by which LTH adult and near-term fetal sheep can acclimatize to long-term high altitude hypoxia. Our findings suggest that increasing BK channel activity in cerebral myocytes may be a therapeutic target to ameliorate the adverse effects of high altitude in adults or of intrauterine hypoxia in the fetus. ) channels, which are well known to modulate vascular tone and promote vasorelaxation (3,7,13,28).In contrast with the role of BK channels in mediating cerebrovascular response to short-term hypoxia, their role in acclimatization to long-term hypoxia (LTH) is less well known. During high-altitude LTH, the CBF in adult humans (23, 60) and sheep (34, 63) returns to normal following a period of transitional increased blood flow, as compiled by Brugniaux et al. (8). The ovine near-term fetus diverts an increased fraction of total cardiac output to the brain, when subjected to hypoxia during gestation. This implies that the cerebral vasculature is more dilated than the systemic vasculature (37, 38). Increased vessel dilation was also the major factor contributing to increased CBF and maintenance of oxygenation in human volunteers taken to high altitude or subjected to acute hypoxia at sea level (66). Because increased blood flow correlates directly with increased vessel diameter in mid-cerebral arteries in humans, as reviewed by Ains...

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Section: Discussionmentioning

confidence: 99%

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

Xing

Lin

Thorington

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…BK channels are formed by four a subunits 4 and regulated by four types of b subunits in various tissues 5 . It is uniquely activated by both membrane depolarization and increased intracellular Ca 2 þ levels 6 , thereby functioning as a neuronal calcium sensor and regulating neurotransmitter release and neuronal excitability [7][8][9][10] . Gain-of-function mutations in BK channel pore-forming a subunit 11 or deletion of the regulatory b4 subunit 12 can lead to enhanced channel activation and development of epilepsy in patients.…”

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confidence: 99%

CRL4ACRBN E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis

et al. 2014

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Ion channels regulate membrane excitation, and mutations of ion channels often cause serious neurological disorders including epilepsy. Compared with extensive analyses of channel protein structure and function, much less is known about the fine tuning of channel activity by post-translational modification. Here we report that the large conductance, Ca 2 þ -and voltage-activated K þ (BK) channels are targeted by the E3 ubiquitin ligase CRL4A CRBN for polyubiquitination and retained in the endoplasmic reticulum (ER). Inactivation of CRL4A CRBN releases deubiquitinated BK channels from the ER to the plasma membrane, leading to markedly enhanced channel activity. Mice with CRL4A CRBN mutation in the brain or treated with a CRL4A CRBN inhibitor are very sensitive to seizure induction, which can be attenuated by blocking BK channels. Finally, the mutant mice develop spontaneous epilepsy when aged. Therefore, ubiquitination of BK channels before their cell surface expression is an important step to prevent systemic neuronal excitability and epileptogenesis.

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“…There are two established types of Ca 2+ -activated K + (KCa) channels in CNS neurons: small conductance (SK, KCa2.x) and big conductance (BK, KCa1.1) (3,4). A third class of intermediate conductance (KCa3.1, SK4, IK1) KCa channel is thought to be expressed only in microglia and endothelial cells in the CNS (3,5,6).…”

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confidence: 99%

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

Engbers

Anderson²,

Asmara³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

100

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Encoding sensory input requires the expression of postsynaptic ion channels to transform key features of afferent input to an appropriate pattern of spike output. Although Ca 2+ -activated K + channels are known to control spike frequency in central neurons, Ca 2+ -activated K + channels of intermediate conductance (KCa3.1) are believed to be restricted to peripheral neurons. We now report that cerebellar Purkinje cells express KCa3.1 channels, as evidenced through single-cell RT-PCR, immunocytochemistry, pharmacology, and single-channel recordings. Furthermore, KCa3.1 channels coimmunoprecipitate and interact with low voltage-activated Cav3.2 Ca 2+ channels at the nanodomain level to support a previously undescribed transient voltage-and Ca 2+ -dependent current. As a result, subthreshold parallel fiber excitatory postsynaptic potentials (EPSPs) activate Cav3 Ca 2+ influx to trigger a KCa3.1-mediated regulation of the EPSP and subsequent after-hyperpolarization. The Cav3-KCa3.1 complex provides powerful control over temporal summation of EPSPs, effectively suppressing low frequencies of parallel fiber input. KCa3.1 channels thus contribute to a high-pass filter that allows Purkinje cells to respond preferentially to high-frequency parallel fiber bursts characteristic of sensory input.C entral neurons receive an enormous number of spontaneously active synaptic inputs, but exhibit the capacity to differentiate features of sensory input from background noise. Cerebellar Purkinje cells are contacted by up to ∼150,000 parallel fibers from granule cells, of which only a subset will convey sensory information at any given time. The activation of a peripheral receptive field is transmitted to the cerebellar cortex by mossy fibers in the form of high-frequency spike bursts (1). The resulting temporal summation of excitatory postsynaptic potentials (EPSPs) generates a similar high-frequency burst in granule cells (2). Purkinje cells should then also possess the means to respond effectively to bursts of parallel fiber input that convey sensory information compared with background activity.Postsynaptic membrane excitability can be controlled by activation of K + channels. There are two established types of Ca 2+ -activated K + (KCa) channels in CNS neurons: small conductance (SK, KCa2.x) and big conductance (BK, KCa1.1) (3, 4). A third class of intermediate conductance (KCa3.1, SK4, IK1) KCa channel is thought to be expressed only in microglia and endothelial cells in the CNS (3, 5, 6). KCa3.1 channels are gated by calmodulin in a similar manner to KCa2.x channels but are insensitive to block by apamin and tetraethylammonium (TEA) (6-8). Instead, the KCa3.1 α-subunit, encoded by the gene KCNN4, has specific residues that bind charybdotoxin and 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) (5-7, 9, 10).In cerebellar Purkinje cells, KCa1.1 and KCa2.2 channels are activated during a spike by high voltage-activated (HVA) P-type Ca 2+ channels (11). In contrast, low voltage-activated (LVA) Cav3 (T-type) Ca 2+ channe...

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Ca²⁺-Activated K⁺Channels: From Protein Complexes to Function

Cited by 229 publications

References 253 publications

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

CRL4ACRBN E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

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Ca2+-Activated K+Channels: From Protein Complexes to Function

Cited by 229 publications

References 253 publications

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle

CRL4ACRBN E3 ubiquitin ligase restricts BK channel activity and prevents epileptogenesis

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells

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Ca²⁺-Activated K⁺Channels: From Protein Complexes to Function