Mg
            <sup>2+</sup>
            mediates interaction between the voltage sensor and cytosolic domain to activate BK channels

Yang, Huanghe; Hu, Lei; Shi, Jingyi; Delaloye, Kelli; Horrigan, Frank T.; Cui, Jianmin

doi:10.1073/pnas.0705873104

Cited by 67 publications

(154 citation statements)

References 44 publications

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“…This result is consistent with the location of D367 that is close to the VSD of the channel in the membrane (9,10). Previous results have demonstrated that the cytosolic domain interacts with the VSD during BK channel activation (28,29), and such interactions may result in a weak voltage dependence of Ca 2+ sensitivity derived from the RCK1 site (17). Thus, it is possible that the mutation D367A also alters function of the VSD, resulting in changes of voltage-dependent activation.…”

Section: +supporting

confidence: 78%

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Ion sensing in the RCK1 domain of BK channels

Zhang

Huang

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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BK-type K + channels are activated by voltage and intracellular Ca 2+ , which is important in modulating muscle contraction, neural transmission, and circadian pacemaker output. Previous studies suggest that the cytosolic domain of BK channels contains two different Ca 2+ binding sites, but the molecular composition of one of the sites is not completely known. Here we report, by systematic mutagenesis studies, the identification of E535 as part of this Ca 2+ binding site. This site is specific for binding to Ca 2+ but not Cd 2+. Experimental results and molecular modeling based on the X-ray crystallographic structures of the BK channel cytosolic domain suggest that the binding of Ca 2+ by the side chains of E535 and the previously identified D367 changes the conformation around the binding site and turns the side chain of M513 into a hydrophobic core, providing a basis to understand how Ca 2+ binding at this site opens the activation gate of the channel that is remotely located in the membrane. ] i . Because of this function, BK channels are important modulators of muscle contraction (1), neuronal spike frequency adaptation (2), neurotransmitter release (3), and circadian pacemaker output (4). BK channels are formed by four Slo1 subunits (5, 6). Each Slo1 contains a membrane-spanning domain, which comprises the pore-gate domain (PGD) and the voltage sensing domain (VSD), and a cytosolic domain (CTD) (7,8), which is made of two regulating domains for K + conductance (RCK1 and RCK2) (9, 10). Intracellular Ca 2+ binds to the CTD to activate the channel by enhancing the open probability of the activation gate located in the membrane-spanning PGD.Previous studies have identified two putative Ca 2+ binding sites in the CTD of BK channels, one is the Ca 2+ bowl located in the RCK2 domain (10-13) and the other is located in the RCK1 domain including the residue D367 (14). The existence of two distinctively different high-affinity Ca 2+ binding sites that are responsible for Ca 2+ -dependent activation of BK channels has been demonstrated in various experimental studies (15). These studies demonstrated that Ca 2+ binding to the two sites activates channel independently with only a small cooperativity (14,16,17), and the two sites show differences in various properties including affinities for Ca 2+ (14, 17), voltage dependence (17), and the molecular mechanisms of coupling to the activation gate (18). The distinction between the properties of the two putative Ca 2+ binding sites may lead to different physiological roles of these sites. For instance, a mutation in Slo1 that is associated with epilepsy and dyskinesia in human (19) specifically enhances the coupling of the RCK1 site to the activation gate to increase Ca 2+ sensitivity of channel activation (18). Although previous studies showed that the Ca 2+ binding site in RCK1 is important for physiological functions, its molecular identity is less certain than that of the Ca 2+ bowl. In the Ca 2+ bowl, previous mutagenesis studies (13) and a recently published X-ray cr...

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Section: +supporting

confidence: 78%

“…The Mg 2+ ion bound to the interface between the VSD and RCK1 activates the BK channel by an electrostatic repulsion to the S4 segment (28). These results suggest that RCK1 is located close to the VSD and the two domains interact intimately, which is corroborated by an electron cryomicroscopy (cryo-EM) structure of BK channels (33).…”

Section: +supporting

confidence: 64%

Ion sensing in the RCK1 domain of BK channels

Zhang

Huang

Yang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies showed that Mg 2ϩ binds at VSD-CTD interface of Slo1 channels with two coordinate residues (D99 and N172) from VSD and another two (E374 and E399) from CTD ( Fig. 1; Shi et al, 2002;Xia et al, 2002;Yang et al, 2008a). The bound Mg 2ϩ interacts with gating charge R213 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies showed that Mg 2ϩ binds in between the VSD and CTD interface of Slo1 and interacts with gating charge R213 in S4 to activate the channel (Yang et al, 2007(Yang et al, , 2008aFig. 1).…”

Section: Introductionmentioning

confidence: 99%

The Interface between Membrane-Spanning and Cytosolic Domains in Ca2+-Dependent K+ Channels Is Involved in Subunit Modulation of Gating

Sun¹,

Shi²,

Delaloye³

et al. 2013

Journal of Neuroscience

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Large-conductance, voltage-, and Ca 2ϩ -dependent K ϩ (BK) channels are broadly expressed in various tissues to modulate neuronal activity, smooth muscle contraction, and secretion. BK channel activation depends on the interactions among the voltage sensing domain (VSD), the cytosolic domain (CTD), and the pore gate domain (PGD) of the Slo1 ␣-subunit, and is further regulated by accessory ␤ subunits (␤1-␤4). How ␤ subunits fine-tune BK channel activation is critical to understand the tissue-specific functions of BK channels. Multiple sites in both Slo1 and the ␤ subunits have been identified to contribute to the interaction between Slo1 and the ␤ subunits. However, it is unclear whether and how the interdomain interactions among the VSD, CTD, and PGD are altered by the ␤ subunits to affect channel activation. Here we show that human ␤1 and ␤2 subunits alter interactions between bound Mg 2ϩ and gating charge R213 and disrupt the disulfide bond formation at the VSD-CTD interface of mouse Slo1, indicating that the ␤ subunits alter the VSD-CTD interface. Reciprocally, mutations in the Slo1 that alter the VSD-CTD interaction can specifically change the effects of the ␤1 subunit on the Ca 2ϩ activation and of the ␤2 subunit on the voltage activation. Together, our data suggest a novel mechanism by which the ␤ subunits modulated BK channel activation such that a ␤ subunit may interact with the VSD or the CTD and alter the VSD-CTD interface of the Slo1, which enables the ␤ subunit to have effects broadly on both voltage and Ca 2ϩ -dependent activation.

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“…However, the mechanism seems to be another: bound Mg 2+ is suggested to electrostatically repel one of the positively charged arginines in the C-terminal part of S4 [219,220]. This shows that cytosolic domains can be close enough to the VSD to have an electrostatic impact.…”

Section: Binding Of Cyclic Nucleotides and Ca 2+ To Specific Domainsmentioning

confidence: 99%

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Börjesson

Elinder

2008

Cell Biochem Biophys

121

146

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Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensing domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensing domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves ~13 Å outwards and rotates ~180º, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane.This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.3

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Mg ²⁺ mediates interaction between the voltage sensor and cytosolic domain to activate BK channels

Cited by 67 publications

References 44 publications

Ion sensing in the RCK1 domain of BK channels

Ion sensing in the RCK1 domain of BK channels

The Interface between Membrane-Spanning and Cytosolic Domains in Ca2+-Dependent K+ Channels Is Involved in Subunit Modulation of Gating

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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Mg 2+ mediates interaction between the voltage sensor and cytosolic domain to activate BK channels

Cited by 67 publications

References 44 publications

Ion sensing in the RCK1 domain of BK channels

Ion sensing in the RCK1 domain of BK channels

The Interface between Membrane-Spanning and Cytosolic Domains in Ca2+-Dependent K+ Channels Is Involved in Subunit Modulation of Gating

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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Mg ²⁺ mediates interaction between the voltage sensor and cytosolic domain to activate BK channels