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BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output.

ABSTRACT: Spontaneous action potentials in the suprachiasmatic nucleus (SCN) are necessary for normal circadian timing of behavior in mammals. The SCN exhibits a daily oscillation in spontaneous firing rate (SFR), but the ionic conductances controlling SFR and the relationship of SFR to subsequent circadian behavioral rhythms are not understood. We show that daily expression of the large conductance Ca(2+)-activated K(+) channel (BK) in the SCN is controlled by the intrinsic circadian clock. BK channel-null mice (Kcnma1(-/-)) have increased SFRs in SCN neurons selectively at night and weak circadian amplitudes in multiple behaviors timed by the SCN. Kcnma1(-/-) mice show normal expression of clock genes such as Arntl (Bmal1), indicating a role for BK channels in SCN pacemaker output, rather than in intrinsic time-keeping. Our findings implicate BK channels as important regulators of the SFR and suggest that the SCN pacemaker governs the expression of circadian behavioral rhythms through SFR modulation.

SUBMITTER: Meredith AL

PROVIDER: S-EPMC2909323 | biostudies-literature | 2006 Aug

REPOSITORIES: biostudies-literature

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BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output.

Meredith Andrea L AL Wiler Steven W SW Miller Brooke H BH Takahashi Joseph S JS Fodor Anthony A AA Ruby Norman F NF Aldrich Richard W RW

Nature neuroscience 20060716 8

Spontaneous action potentials in the suprachiasmatic nucleus (SCN) are necessary for normal circadian timing of behavior in mammals. The SCN exhibits a daily oscillation in spontaneous firing rate (SFR), but the ionic conductances controlling SFR and the relationship of SFR to subsequent circadian behavioral rhythms are not understood. We show that daily expression of the large conductance Ca(2+)-activated K(+) channel (BK) in the SCN is controlled by the intrinsic circadian clock. BK channel-nu ...[more]

PMID: 16845385

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Project description:Background: Ion channels are key determinants for the function of excitable cells but little is known about their role and involvement during cardiac development. Earlier work identified Ca2+-activated potassium channels of small and intermediate conductance (SKCas) as important regulators of neural stem cell fate. Here, we have investigated their impact on the differentiation of pluripotent cells towards the cardiac lineage. Methods and Results: We have applied the SKCa-activator EBIO on embryonic stem cells and identified this particular ion channel family as a new critical target involved in the generation of cardiac pacemaker-like cells: SKCa-activation led to rapid remodeling of the actin cytoskeleton, inhibition of proliferation, induction of differentiation and diminished teratoma formation. Time-restricted SKCa-activation induced cardiac mesoderm and commitment to the cardiac lineage as shown by gene regulation, protein and functional electrophysiological studies. In addition, the differentiation into cardiomyocytes was modulated in a qualitative fashion, resulting in a strong enrichment of pacemaker-like cells. This was accompanied by induction of the sino-atrial gene program and in parallel by a loss of the chamber-specific myocardium. In addition, SKCa activity induced activation of the Ras-Mek-Erk signaling cascade, a signaling pathway involved in the EBIO-induced effects. Conclusions: SKCa-activation drives the fate of pluripotent cells towards the cardiac lineage and preferentially into pacemaker-like cardiomyocytes. This provides a novel strategy for the enrichment of cardiomyocytes and in particular, the generation of a specific subtype of cardiomyocytes, pacemaker-like cells, without genetic modification. Untreated ES cells in three independent experiments: - Untreated control ES cells sample 1 (Con_1) - Untreated control ES cells sample 2 (Con_2) - Untreated control ES cells sample 3 (Con_3) EBIO-treated ES cells in three independent experiments: - EBIO-treated ES cells sample 1 (EBIO_1) - EBIO-treated ES cells sample 2 (EBIO_2) - EBIO-treated ES cells sample 3 (EBIO_3) Untreated differentiated ES cells in two independent experiments: - Untreated control differentiated ES cells sample 1 (Con_day5+10_1) - Untreated control differentiated ES cells sample 2 (Con_day5+10_2) EBIO-treated differentiated ES cells in two independent experiments: - EBIO-treated differentiated ES cells sample 1 (EBIO_day5+10_1) - EBIO-treated differentiated ES cells sample 2 (EBIO_day5+10_2)

Project description:Calcium-activated, large conductance potassium (BK) channels in tetrapods are encoded by a single slo1 gene, which undergoes extensive alternative splicing. Alternative splicing generates a high level of functional diversity in BK channels that contributes to the wide range of frequencies electrically tuned by the inner ear hair cells of many tetrapods. To date, the role of BK channels in hearing among teleost fishes has not been investigated at the molecular level, although teleosts account for approximately half of all extant vertebrate species. We identified slo1 genes in teleost and nonteleost fishes using polymerase chain reaction and genetic sequence databases. In contrast to tetrapods, all teleosts examined were found to express duplicate slo1 genes in the central nervous system, whereas nonteleosts that diverged prior to the teleost whole-genome duplication event express a single slo1 gene. Phylogenetic analyses further revealed that whereas other slo1 duplicates were the result of a single duplication event, an independent duplication occurred in a basal teleost (Anguilla rostrata) following the slo1 duplication in teleosts. A third, independent slo1 duplication (autotetraploidization) occurred in salmonids. Comparison of teleost slo1 genomic sequences to their tetrapod orthologue revealed a reduced number of alternative splice sites in both slo1 co-orthologues. For the teleost Porichthys notatus, a focal study species that vocalizes with maximal spectral energy in the range electrically tuned by BK channels in the inner ear, peripheral tissues show the expression of either one (e.g., vocal muscle) or both (e.g., inner ear) slo1 paralogues with important implications for both auditory and vocal physiology. Additional loss of expression of one slo1 paralogue in nonneural tissues in P. notatus suggests that slo1 duplicates were retained via subfunctionalization. Together, the results predict that teleost fish achieve a diversity of BK channel subfunction via gene duplication, rather than increased alternative splicing as witnessed for the tetrapod and invertebrate orthologue.

Dataset Information

BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output.

Publications

BK calcium-activated potassium channels regulate circadian behavioral rhythms and pacemaker output.

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