New Disguises for an Old Channel: MaxiK Channel β-Subunits

Orio, Patricio; Rojas, Patricio; Ferreira, Gonzalo; Latorre, Ramón

doi:10.1152/nips.01387.2002

Cited by 237 publications

(350 citation statements)

References 20 publications

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“…The BK channel consists of four ␣ subunits and four optional auxiliary ␤ subunits (17). The poreforming ␣ subunit is encoded by only a single gene, KCNMA1 (also called Slo), from which multiple splice isoforms are generated (18,19), whereas there are four different ␤ subunit genes with tissue-specific expression (20)(21)(22)(23).…”

Section: Resultsmentioning

confidence: 99%

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

Sausbier

Hu²,

Arntz³

et al. 2004

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

380

423

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Malfunctions of potassium channels are increasingly implicated as causes of neurological disorders. However, the functional roles of the large-conductance voltage-and Ca 2؉ -activated K ؉ channel (BK channel), a unique calcium, and voltage-activated potassium channel type have remained elusive. Here we report that mice lacking BK channels (BK ؊/؊ ) show cerebellar dysfunction in the form of abnormal conditioned eye-blink reflex, abnormal locomotion and pronounced deficiency in motor coordination, which are likely consequences of cerebellar learning deficiency. At the cellular level, the BK ؊/؊ mice showed a dramatic reduction in spontaneous activity of the BK ؊/؊ cerebellar Purkinje neurons, which generate the sole output of the cerebellar cortex and, in addition, enhanced short-term depression at the only output synapses of the cerebellar cortex, in the deep cerebellar nuclei. The impairing cellular effects caused by the lack of postsynaptic BK channels were found to be due to depolarization-induced inactivation of the action potential mechanism. These results identify previously unknown roles of potassium channels in mammalian cerebellar function and motor control. In addition, they provide a previously undescribed animal model of cerebellar ataxia. P otassium channels are the largest and most diverse class of ion channels underlying electrical signaling in the brain (1). By causing highly regulated, time-dependent, and localized polarization of the cell membrane, the opening of K ϩ channels mediates feedback control of excitability in a variety of cell types and conditions (1). Consequently, K ϩ channel dysfunctions can cause a range of neurological disorders (2-6), and drugs that target K ϩ channels hold promise for a variety of clinical applications (7).Among the wide range of voltage-and calcium-gated K ϩ channel types, one stands out as unique: the large-conductance voltage-and Ca 2ϩ -activated K ϩ channel (BK channel, also termed Slo or Maxi-K) differs from all other K ϩ channels in that it can be activated by both intracellular Ca 2ϩ ions and membrane depolarization (8). These channels are widely expressed in central and peripheral neurons, as well as in other tissues (9), and are regarded as a promising drug target (10). However, the functions of the BK channels in vivo have not previously been directly tested in any vertebrate species. We therefore decided to examine the functions of these channels by inactivating the gene encoding the pore-forming channel protein. MethodsA complete description of the methods is given in Supporting Methods, which is published as supporting information on the PNAS web site.Generation of BK Channel ␣ Subunit-Deficient Mice. In the targeting vector (Fig. 5, which is published as supporting information on the PNAS web site), the pore exon was flanked by a single loxP site and a floxed neo͞tk cassette. Correctly targeted embryonic stem cells were injected into C57BL͞6 blastocysts and resulting chimeric mice mated with C57BL͞6. Homozygous BK-deficient mice (F 2 generation) ...

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Section: Resultsmentioning

confidence: 99%

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

Sausbier

Hu²,

Arntz³

et al. 2004

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

380

423

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“…An important addition to current knowledge on PIP 2 regulation of ion channels is that the fi nal PIP 2 effect is critically determined by channel accessory subunits, and such a mechanism can be subunit specifi c. Moreover, the differential expression of BK accessory subunits across tissues ( Behrens et al, 2000 ;Brenner et al, 2000 ;Orio et al, 2002 ) raises the possibility that a direct PIP 2 modulation of BK channel function is specifi cally relevant in tissues where the ␤ 1 subunit is highly expressed. Indeed, while PIP 2 robustly activates native BK channels in vascular smooth muscle ( Fig.…”

Section: Pathophysiological Implicationsmentioning

confidence: 99%

Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

Vaithianathan¹,

Bukiya²,

Liu³

et al. 2008

J Cell Biol

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“…In mammalian tissues, KCNMA1 is almost ubiquitously expressed along with four regulatory b-subunits KCNMB1-4 (Rebhan et al, 1997;Orio et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer

et al. 2006

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New Disguises for an Old Channel: MaxiK Channel β-Subunits

Cited by 237 publications

References 20 publications

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer

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New Disguises for an Old Channel: MaxiK Channel β-Subunits

Cited by 237 publications

References 20 publications

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca 2+ -activated K + channel deficiency

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca 2+ -activated K + channel deficiency

Direct Regulation of BK Channels by Phosphatidylinositol 4,5-Bisphosphate as a Novel Signaling Pathway

KCNMA1 gene amplification promotes tumor cell proliferation in human prostate cancer

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Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency

Cerebellar ataxia and Purkinje cell dysfunction caused by Ca ²⁺ -activated K ⁺ channel deficiency