Regulation of Voltage-Activated K+ Channel Gating by Transmembrane β Subunits

Sun, Xinwei; Zaydman, Mark A.; Cui, Jianmin

doi:10.3389/fphar.2012.00063

Cited by 48 publications

(47 citation statements)

References 151 publications

(226 reference statements)

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“…In large part, diversity is mediated by families of accessory ␤-and ␥-subunits that regulate BK channel biophysical properties and pharmacology (recent reviews, Sun et al 2012;Yan and Aldrich 2012). BK channels have a long-established role in repolarizing action potentials (APs) and contributing to the fast afterhyperpolarization (fAHP) in many neurons (Sah 1996;Sah and Faber 2002).…”

Section: Given Their Broad Expression These Findings May Be Relevantmentioning

confidence: 99%

Knockout of the BK β₄-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability

Wang

Bugay

Ling

et al. 2016

Journal of Neurophysiology

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Knockout of the BK ␤ 4 -subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability. J Neurophysiol 116: 456 -465, 2016. First published May 4, 2016 doi:10.1152/jn.00857.2015.-BK channels are large-conductance calcium-and voltage-activated potassium channels with diverse properties. Knockout of the accessory BK ␤ 4 -subunit in hippocampus dentate gyrus granule neurons causes BK channels to change properties from slow-gated type II channels to fast-gated type I channels that sharpen the action potential, increase the fast afterhyperpolarization (fAHP) amplitude, and increase spike frequency. Here we studied the calcium channels that contribute to fast-gated BK channel activation and increased excitability of ␤ 4 knockout neurons. By using pharmacological blockers during currentclamp recording, we find that BK channel activation during the fAHP is dependent on ryanodine receptor activation. In contrast, L-type calcium channel blocker (nifedipine) affects the BK channel-dependent repolarization phase of the action potential but has no effect on the fAHP. Reducing BK channel activation during the repolarization phase with nifedipine, or during the fAHP with ryanodine, indicated that it is the BK-mediated increase of the fAHP that confers proexcitatory effects. The proexcitatory role of the fAHP was corroborated using dynamic current clamp. Increase or decrease of the fAHP amplitude during spiking revealed an inverse relationship between fAHP amplitude and interspike interval. Finally, we show that the seizure-prone ryanodine receptor gain-of-function (R2474S) knockin mice have an unaltered repolarization phase but larger fAHP and increased AP frequency compared with their control littermates. In summary, these results indicate that an important role of the ␤ 4 -subunit is to reduce ryanodine receptor-BK channel functional coupling during the fAHP component of the action potential, thereby decreasing excitability of dentate gyrus neurons.large-conductance calcium-and voltage-activated potassium channels; action potentials; dentate gyrus; fast afterhyperpolarization

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Section: Given Their Broad Expression These Findings May Be Relevantmentioning

confidence: 99%

Knockout of the BK β₄-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability

Wang

Bugay

Ling

et al. 2016

Journal of Neurophysiology

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“…Regulatory β subunits associate with Kv channels to modulate the gating properties of Kv channels 2 . KCNQ1 (Kv7.1 or KvLQT1) is expressed in many different tissues, such as the inner ear, the kidney, and the heart 3 .…”

Section: Introductionmentioning

confidence: 99%

KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps

et al. 2014

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The functional properties of KCNQ1 channels are highly dependent on associated KCNE β subunits. Mutations in KCNQ1 or KCNE subunits can cause congenital channelopathies, such as deafness, cardiac arrhythmias, and epilepsy. The mechanism by which KCNE1 beta subunits slow the kinetics of KCNQ1 channels is a matter of current controversy. Here we show that KCNQ1/KCNE1 channel activation occurs in two steps: first, mutually independent voltage sensor movements in the four KCNQ1 subunits generate the main gating charge movement and underlie the initial delay in the activation time course of KCNQ1/KCNE1 currents. Second, a slower and concerted conformational change of all four voltage sensors and the gate, which opens the KCNQ1/KCNE1 channel. Our data show that KCNE1 divides the voltage sensor movement into two steps with widely different voltage dependences and kinetics. The two voltage sensor steps in KCNQ1/KCNE1 channels can be pharmacologically isolated and further separated by a disease-causing mutation.

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“…KCNQ1 asubunits can interact with any one of the five KCNE auxiliary bsubunits, resulting in different channel functional characteristics (Abbott et al, 2001;Nakajo and Kubo, 2011;Sun et al, 2012;Wrobel et al, 2012). Co-assembly of KCNQ1 with KCNE1 generates the I KS K + current that is vital for the proper repolarization of the cardiac action potential (Barhanin et al, 1996;Nerbonne and Kass, 2005;Sanguinetti et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Long QT mutations disrupt IKS regulation by PKA and PIP2 at the same KCNQ1 helix C-KCNE1 interface

Dvir

Strulovich

Sachyani

et al. 2014

Journal of Cell Science

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KCNQ1 and KCNE1 co-assembly generates the I KS K + current, which is crucial to the cardiac action potential repolarization. Mutations in their corresponding genes cause long QT syndrome (LQT) and atrial fibrillation. The A-kinase anchor protein, yotiao (also known as AKAP9), brings the I KS channel complex together with signaling proteins to achieve regulation upon b1-adrenergic stimulation. Recently, we have shown that KCNQ1 helix C interacts with the KCNE1 distal C-terminus. We postulated that this interface is crucial for I KS channel modulation. Here, we examined the yet unknown molecular mechanisms of LQT mutations located at this intracellular intersubunit interface. All LQT mutations disrupted the internal KCNQ1-KCNE1 intersubunit interaction. LQT mutants in KCNQ1 helix C led to a decreased current density and a depolarizing shift of channel activation, mainly arising from impaired phosphatidylinositol-4,5-bisphosphate (PIP 2 ) modulation. In the KCNE1 distal C-terminus, the LQT mutation P127T suppressed yotiao-dependent cAMP-mediated upregulation of the I KS current, which was caused by reduced KCNQ1 phosphorylation at S27. Thus, KCNQ1 helix C is important for channel modulation by PIP 2 , whereas the KCNE1 distal C-terminus appears essential for the regulation of I KS by yotiao-mediated PKA phosphorylation.

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Regulation of Voltage-Activated K+ Channel Gating by Transmembrane β Subunits

Cited by 48 publications

References 151 publications

Knockout of the BK β₄-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability

Knockout of the BK β₄-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability

KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps

Long QT mutations disrupt IKS regulation by PKA and PIP2 at the same KCNQ1 helix C-KCNE1 interface

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Regulation of Voltage-Activated K+ Channel Gating by Transmembrane β Subunits

Cited by 48 publications

References 151 publications

Knockout of the BK β4-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability

Knockout of the BK β4-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability

KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps

Long QT mutations disrupt IKS regulation by PKA and PIP2 at the same KCNQ1 helix C-KCNE1 interface

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Knockout of the BK β₄-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability

Knockout of the BK β₄-subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability