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Repolarizing responses of BKCa-Cav complexes are distinctly shaped by their Cav subunits.

ABSTRACT: Large-conductance Ca(2+)- and voltage-activated potassium (BK(Ca)) channels shape the firing pattern in many types of excitable cell through their repolarizing K(+) conductance. The onset and duration of the BK(Ca)-mediated currents typically initiated by action potentials (APs) appear to be cell-type specific and were shown to vary between 1 ms and up to a few tens of milliseconds. In recent work, we showed that reliable activation of BK(Ca) channels under cellular conditions is enabled by their integration into complexes with voltage-activated Ca(2+) (Cav) channels that provide Ca(2+) ions at concentrations sufficiently high (> or =10 microM) for activation of BK(Ca) in the physiological voltage range. Formation of BK(Ca)-Cav complexes is restricted to a subset of Cav channels, Cav1.2 (L-type) and Cav2.1/2.2 (P/Q- and N-type), which differ greatly in their expression pattern and gating properties. Here, we reconstituted distinct BK(Ca)-Cav complexes in Xenopus oocytes and culture cells and used patch-clamp recordings to compare the functional properties of BK(Ca)-Cav1.2 and BK(Ca)-Cav2.1 complexes. Under steady-state conditions, K(+) currents mediated by BK(Ca)-Cav2.1 complexes exhibit a considerably faster rise time and reach maximum at potentials markedly more negative than complexes formed by BK(Ca) and Cav1.2, in line with the distinct steady-state activation and gating kinetics of the two Cav subtypes. When AP waveforms were used as a voltage command, K(+) currents mediated by BK(Ca)-Cav2.1 occurred at shorter APs and lasted longer than that of BK(Ca)-Cav1.2. These results demonstrate that the repolarizing K(+) currents through BK(Ca)-Cav complexes are shaped by the respective Cav subunit and that the distinct Cav channels may adapt BK(Ca) currents to the particular requirements of distinct types of cell.

SUBMITTER: Berkefeld H

PROVIDER: S-EPMC6670555 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Repolarizing responses of BKCa-Cav complexes are distinctly shaped by their Cav subunits.

Berkefeld Henrike H Fakler Bernd B

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080801 33

Large-conductance Ca(2+)- and voltage-activated potassium (BK(Ca)) channels shape the firing pattern in many types of excitable cell through their repolarizing K(+) conductance. The onset and duration of the BK(Ca)-mediated currents typically initiated by action potentials (APs) appear to be cell-type specific and were shown to vary between 1 ms and up to a few tens of milliseconds. In recent work, we showed that reliable activation of BK(Ca) channels under cellular conditions is enabled by thei ...[more]

PMID: 18701686

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Project description:Large conductance voltage- and Ca2+-activated K+ (BKCa) channels are essential regulators of membrane excitability in a wide variety of cells and tissues. An important mechanism of modulation of BKCa channel activity is its association with auxiliary subunits. In smooth muscle cells, the most predominant regulatory subunit of BKCa channels is the β1-subunit. We have previously described that BKCa channels with distinctive N-terminal ends (starting with the amino acid sequence MDAL, MSSN or MANG) are differentially modulated by the β1-subunit, but not by the β2. Here we extended our studies to understand how the distinct N-terminal regions differentially modulate channel activity by β-subunits. We recorded inside-out single-channel currents from HEK293T cells co-expressing the BKCa containing three N-terminal sequences with two β1-β2 chimeric constructs containing the extracellular loop of β1 or β2, and the transmembrane and cytoplasmic domains of β2 or β1, respectively. Both β chimeric constructs induced leftward shifts of voltage-activation curves of channels starting with MANG and MDAL, in the presence of 10 or 100 μM intracellular Ca2+. However, MSSN showed no shift of the voltage-activation, at the same Ca2+ concentrations. The presence of the extracellular loop of β1 in the chimera resembled results seen with the full β1 subunit, suggesting that the extracellular region of β1 might be responsible for the lack of modulation observed in MSSN. We further studied a poly-serine stretch present in the N-terminal region of MSSN and observed that the voltage-activation curves of BKCa channels either containing or lacking this poly-serine stretch were leftward shifted by β1-subunit in a similar way. Overall, our results provide further insights into the mechanism of modulation of the different N-terminal regions of the BKCa channel by β-subunits and highlight the extension of this region of the channel as a form of modulation of channel activity.

Dataset Information

Repolarizing responses of BKCa-Cav complexes are distinctly shaped by their Cav subunits.

Publications

Repolarizing responses of BKCa-Cav complexes are distinctly shaped by their Cav subunits.

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