Dataset Information

Concise Whole-Cell Modeling of BK_Ca-CaV Activity Controlled by Local Coupling and Stoichiometry.

ABSTRACT: Large-conductance Ca²⁺-dependent K⁺ (BK_Ca) channels are important regulators of electrical activity. These channels colocalize and form ion channel complexes with voltage-dependent Ca²⁺ (CaV) channels. Recent stochastic simulations of the BK_Ca-CaV complex with 1:1 stoichiometry have given important insight into the local control of BK_Ca channels by fluctuating nanodomains of Ca²⁺. However, such Monte Carlo simulations are computationally expensive, and are therefore not suitable for large-scale simulations of cellular electrical activity. In this work we extend the stochastic model to more realistic BK_Ca-CaV complexes with 1:n stoichiometry, and analyze the single-complex model with Markov chain theory. From the description of a single BK_Ca-CaV complex, using arguments based on timescale analysis, we derive a concise model of whole-cell BK_Ca currents, which can readily be analyzed and inserted into models of cellular electrical activity. We illustrate the usefulness of our results by inserting our BK_Ca description into previously published whole-cell models, and perform simulations of electrical activity in various cell types, which show that BK_Ca-CaV stoichiometry can affect whole-cell behavior substantially. Our work provides a simple formulation for the whole-cell BK_Ca current that respects local interactions in BK_Ca-CaV complexes, and indicates how local-global coupling of ion channels may affect cell behavior.

SUBMITTER: Montefusco F

PROVIDER: S-EPMC5474739 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Concise Whole-Cell Modeling of BKCa-CaV Activity Controlled by Local Coupling and Stoichiometry.

Montefusco Francesco F Tagliavini Alessia A Ferrante Marco M Pedersen Morten Gram MG

Biophysical journal 20170601 11

Large-conductance Ca2+-dependent K+ (BKCa) channels are important regulators of electrical activity. These channels colocalize and form ion channel complexes with voltage-dependent Ca2+ (CaV) channels. Recent stochastic simulations of the BKCa-CaV complex with 1:1 stoichiometry have given important insight into the local control of BKCa channels by fluctuating nanodomains of Ca2+. However, such Monte Carlo simulations a ...[more]

PMID: 28591611

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Project description:Mammalian circadian (24 h) rhythms are timed by the pattern of spontaneous action potential firing in the suprachiasmatic nucleus (SCN). This oscillation in firing is produced through circadian regulation of several membrane currents, including large-conductance Ca2+- and voltage-activated K+ (BK) and L-type Ca2+ channel (LTCC) currents. During the day steady-state BK currents depend mostly on LTCCs for activation, whereas at night they depend predominantly on ryanodine receptors (RyRs). However, the contribution of these Ca2+ channels to BK channel activation during action potential firing has not been thoroughly investigated. In this study, we used a pharmacological approach to determine that both LTCCs and RyRs contribute to the baseline membrane potential of SCN action potential waveforms, as well as action potential-evoked BK current, during the day and night, respectively. Since the baseline membrane potential is a major determinant of circadian firing rate, we focused on the LTCCs contributing to low voltage activation of BK channels during the subthreshold phase. For these experiments, two LTCC subtypes found in SCN (CaV1.2 and CaV1.3) were coexpressed with BK channels in heterologous cells, where their differential contributions could be separately measured. CaV1.3 channels produced currents that were shifted to more hyperpolarized potentials compared with CaV1.2, resulting in increased subthreshold Ca2+ and BK currents during an action potential command. These results show that although multiple Ca2+ sources in SCN can contribute to the activation of BK current during an action potential, specific BK-CaV1.3 partnerships may optimize the subthreshold BK current activation that is critical for firing rate regulation.NEW & NOTEWORTHY BK K+ channels are important regulators of firing. Although Ca2+ channels are required for their activation in excitable cells, it is not well understood how BK channels activate using these Ca2+ sources during an action potential. This study demonstrates the differences in BK current activated by CaV1.2 and CaV1.3 channels in clock neurons and heterologous cells. The results define how specific ion channel partnerships can be engaged during distinct phases of the action potential.

Dataset Information

Concise Whole-Cell Modeling of BK_Ca-CaV Activity Controlled by Local Coupling and Stoichiometry.

Publications

Concise Whole-Cell Modeling of BK<sub>Ca</sub>-CaV Activity Controlled by Local Coupling and Stoichiometry.

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