N-terminal Isoforms of the Large-conductance Ca2+-activated K+ Channel Are Differentially Modulated by the Auxiliary β1-Subunit

Lorca, Ramón A.; Stamnes, Susan J.; Pillai, Meghan K.; Hsiao, Jordy J.; Wright, M.; England, Sarah K.

doi:10.1074/jbc.m113.521526

Cited by 13 publications

(10 citation statements)

References 42 publications

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“…We speculate that the mid and high voltage sensitivities we observed in UA SMCs at P14 and P18 were due to the association of BK Ca with the β1and γ1-subunits, respectively. The mid voltage sensitive channels were activated with a V 0.5 around −40 mV, which is comparable to that found in plasma membrane patches containing BK Ca αand β1-subunits (Lippiat et al 2003;Liu et al 2014;Lorca et al 2014). Although β1-subunit mRNA levels in UAs did not significantly differ between NP, P14 and P18 mice, β1-subunit protein levels may differ.…”

Section: Discussionsupporting

confidence: 74%

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The large‐conductance voltage‐ and Ca²⁺‐activated K⁺ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy

Lorca

Wakle-Prabagaran

Freeman

et al. 2018

The Journal of Physiology

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Insufficient vasodilatation of the uterine artery (UA) during pregnancy leads to poor utero-placental perfusion, contributing to intrauterine growth restriction and fetal loss. Activity of the large-conductance Ca -activated K (BK ) channel increases in the UA during pregnancy, and its inhibition reduces uterine blood flow, highlighting a role of this channel in UA adaptation to pregnancy. The auxiliary γ1-subunit increases BK activation in vascular smooth muscle, but its role in pregnancy-associated UA remodelling is unknown. We explored whether the BK and its γ1-subunit contribute to UA remodelling during pregnancy. Doppler imaging revealed that, compared to UAs from wild-type (WT) mice, UAs from BK knockout (BK ) mice had lower resistance at pregnancy day 14 (P14) but not at P18. Lumen diameters were twofold larger in pressurized UAs from P18 WT mice than in those from non-pregnant mice, but this difference was not seen in UAs from BK mice. UAs from pregnant WT mice constricted 20-50% in response to the BK blocker iberiotoxin (IbTX), whereas UAs from non-pregnant WT mice only constricted 15%. Patch-clamp analysis of WT UA smooth muscle cells confirmed that BK activity increased over pregnancy, showing three distinct voltage sensitivities. The γ1-subunit transcript increased 7- to 10-fold during pregnancy. Furthermore, γ1-subunit knockdown reduced IbTX sensitivity in UAs from pregnant mice, whereas γ1-subunit overexpression increased IbTX sensitivity in UAs from non-pregnant mice. Finally, at P18, γ1-knockout (γ1 ) mice had smaller UA diameters than WT mice, and IbTX-mediated vasoconstriction was prevented in UAs from γ1 mice. Our results suggest that the γ1-subunit increases BK activation in UAs during pregnancy.

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Section: Discussionsupporting

confidence: 74%

“…; Lorca et al . ). Although β1‐subunit mRNA levels in UAs did not significantly differ between NP, P14 and P18 mice, β1‐subunit protein levels may differ.…”

Section: Discussionmentioning

confidence: 97%

The large‐conductance voltage‐ and Ca²⁺‐activated K⁺ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy

Lorca

Wakle-Prabagaran

Freeman

et al. 2018

The Journal of Physiology

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“…Because β1 and β2 subunits modulate the BK Ca channel by different mechanisms [ 40 ], we investigated the effect of β2ND and the β1/β2 chimeric constructs on the kinetics of the BK Ca α-subunit N-terminal constructs. Initially, we investigated the open-state kinetics.…”

Section: Resultsmentioning

confidence: 99%

The unique N-terminal sequence of the BKCa channel α-subunit determines its modulation by β-subunits

Lorca

England

2017

PLoS ONE

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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.

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“…Association with β1 decreases the voltage dependency and enhances the apparent Ca 2+ -sensitivity of the BK Ca channel α-subunits (McManus et al, 1995; Wallner et al, 1995; Tanaka et al, 1997; Lorca et al, 2014). The β1-subunit also modulates the membrane trafficking (Toro et al, 2006; Kim et al, 2007b), mobility (Yamamura et al, 2012), pharmacology (Giangiacomo et al, 2000), and alcohol and estrogen sensitivity (Valverde et al, 1999; Feinberg-Zadek and Treistman, 2007) of the α-subunits.…”

Section: Extrinsic Mechanisms Of Bkca Channel Modulationmentioning

confidence: 99%

“…Their association with one another is not altered at this time (Matharoo-Ball et al, 2003), suggesting that dissociation of BK Ca channels from accessory β1-subunits is not a mechanism to alter channel activity during pregnancy. However, certain variants of the BK Ca channel α-subunit can be modulated differentially by the β1-subunit (Lorca et al, 2014), thus acting to fine tune the properties of BK Ca to best fulfill its cell type-specific functions.…”

Section: Extrinsic Mechanisms Of Bkca Channel Modulationmentioning

confidence: 99%

Functional insights into modulation of BKCa channel activity to alter myometrial contractility

2014

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The large-conductance voltage- and Ca2+-activated K+ channel (BKCa) is an important regulator of membrane excitability in a wide variety of cells and tissues. In myometrial smooth muscle, activation of BKCa plays essential roles in buffering contractility to maintain uterine quiescence during pregnancy and in the transition to a more contractile state at the onset of labor. Multiple mechanisms of modulation have been described to alter BKCa channel activity, expression, and cellular localization. In the myometrium, BKCa is regulated by alternative splicing, protein targeting to the plasma membrane, compartmentation in membrane microdomains, and posttranslational modifications. In addition, interaction with auxiliary proteins (i.e., β1- and β2-subunits), association with G-protein coupled receptor signaling pathways, such as those activated by adrenergic and oxytocin receptors, and hormonal regulation provide further mechanisms of variable modulation of BKCa channel function in myometrial smooth muscle. Here, we provide an overview of these mechanisms of BKCa channel modulation and provide a context for them in relation to myometrial function.

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N-terminal Isoforms of the Large-conductance Ca2+-activated K+ Channel Are Differentially Modulated by the Auxiliary β1-Subunit

Cited by 13 publications

References 42 publications

The large‐conductance voltage‐ and Ca²⁺‐activated K⁺ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy

The large‐conductance voltage‐ and Ca²⁺‐activated K⁺ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy

The unique N-terminal sequence of the BKCa channel α-subunit determines its modulation by β-subunits

Functional insights into modulation of BKCa channel activity to alter myometrial contractility

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N-terminal Isoforms of the Large-conductance Ca2+-activated K+ Channel Are Differentially Modulated by the Auxiliary β1-Subunit

Cited by 13 publications

References 42 publications

The large‐conductance voltage‐ and Ca2+‐activated K+ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy

The large‐conductance voltage‐ and Ca2+‐activated K+ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy

The unique N-terminal sequence of the BKCa channel α-subunit determines its modulation by β-subunits

Functional insights into modulation of BKCa channel activity to alter myometrial contractility

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The large‐conductance voltage‐ and Ca²⁺‐activated K⁺ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy

The large‐conductance voltage‐ and Ca²⁺‐activated K⁺ channel and its γ1‐subunit modulate mouse uterine artery function during pregnancy