Understanding the conformational motions of RCK gating rings

Giráldez, Teresa; Rothberg, Brad S.

doi:10.1085/jgp.201611726

Cited by 21 publications

(15 citation statements)

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“…Previous considerations should be revisited in light of these novel findings, which undoubtedly set an unprecedented ground for SK channels drug discovery. These new IK structures appear barely 1 year after the cryo-EM structures of the full-length BK channel in the open and closed states was obtained ( Hite et al, 2017 ; Tao et al, 2017 ), revealing new and interesting insights in the channel structure–function relationships ( Giraldez and Rothberg, 2017 ; Zhou et al, 2017 ; Kshatri et al, 2018 ). In this context, other techniques such as patch-clamp fluorometry ( Zheng and Zagotta, 2003 ; Wulf and Pless, 2018 ) have proven to be useful tools to study conformational changes between subunits at the level of the gating ring during activation of functional BK channels ( Giraldez et al, 2005 ; Miranda et al, 2013 , 2016 ), and could also be extended to study other members of the K Ca subfamily.…”

Section: Molecular Strategies and Current Challenges To Target K mentioning

confidence: 99%

“…Available crystal structures of the SK CaMBD region bound to CaM have contributed to advance our knowledge about the regulation of these channels by various effectors ( Schumacher et al, 2001 , 2004 ; Zhang et al, 2012a , b , 2013 ; Zhang M. et al, 2014 ; Nam et al, 2017 ). Until very recently, structural information about BK channels was the most extensive, including X-ray crystal structures of the isolated C-terminal region known as the “gating ring” ( Wu et al, 2010 ; Yuan et al, 2011 ) as well as cryo-EM structures of the full-length channel obtained in the presence and absence of Ca 2+ ( Hite et al, 2017 ; Tao et al, 2017 ; see also Giraldez and Rothberg, 2017 ; Zhou et al, 2017 ) ( Figure 1D ). Exciting new results from the MacKinnon laboratory bring now to light the cryo-electron microscopy (cryo-EM) structures of a human IK-CaM complex in closed and activated states, unveiling unprecedented insights about their gating mechanism ( Lee and MacKinnon, 2018 ) ( Figure 1B ).…”

Section: Introductionmentioning

confidence: 99%

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Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Kshatri

Gonzalez-Hernandez

Giráldez

2018

Front. Mol. Neurosci.

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Within the potassium ion channel family, calcium activated potassium (KCa) channels are unique in their ability to couple intracellular Ca2+ signals to membrane potential variations. KCa channels are diversely distributed throughout the central nervous system and play fundamental roles ranging from regulating neuronal excitability to controlling neurotransmitter release. The physiological versatility of KCa channels is enhanced by alternative splicing and co-assembly with auxiliary subunits, leading to fundamental differences in distribution, subunit composition and pharmacological profiles. Thus, understanding specific KCa channels’ mechanisms in neuronal function is challenging. Based on their single channel conductance, KCa channels are divided into three subtypes: small (SK, 4–14 pS), intermediate (IK, 32–39 pS) and big potassium (BK, 200–300 pS) channels. This review describes the biophysical characteristics of these KCa channels, as well as their physiological roles and pathological implications. In addition, we also discuss the current pharmacological strategies and challenges to target KCa channels for the treatment of various neurological and psychiatric disorders.

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Section: Molecular Strategies and Current Challenges To Target K mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Kshatri

Gonzalez-Hernandez

Giráldez

2018

Front. Mol. Neurosci.

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“…Structurally, BK channels are tetramers in which each subunit consists of an N-terminal voltage-sensing domain (VSD; transmembrane helices S0-S4), a pore/gate domain (PGD; transmembrane helices S5-P-S6), and a Ca 2+ -sensing domain (CSD) comprised of two tandem cytosolic RCK domains (Giraldez and Rothberg, 2017). Recently, it was suggested that the BK channel opener Cym04, a dehydroabietic acid derivative, as well as the benzimidazolone derivative NS1619, may act through a mechanism that involves binding to the S6-RCK linker (Gessner et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Molecular mechanism of BK channel activation by the smooth muscle relaxant NS11021

Rockman

Vouga

Rothberg

2020

Journal of General Physiology

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Large-conductance Ca2+-activated K+ channels (BK channels) are activated by cytosolic calcium and depolarized membrane potential under physiological conditions. Thus, these channels control electrical excitability in neurons and smooth muscle by gating K+ efflux and hyperpolarizing the membrane in response to Ca2+ signaling. Altered BK channel function has been linked to epilepsy, dyskinesia, and other neurological deficits in humans, making these channels a key target for drug therapies. To gain insight into mechanisms underlying pharmacological modulation of BK channel gating, here we studied mechanisms underlying activation of BK channels by the biarylthiourea derivative, NS11021, which acts as a smooth muscle relaxant. We observe that increasing NS11021 shifts the half-maximal activation voltage for BK channels toward more hyperpolarized voltages, in both the presence and nominal absence of Ca2+, suggesting that NS11021 facilitates BK channel activation primarily by a mechanism that is distinct from Ca2+ activation. 30 µM NS11021 slows the time course of BK channel deactivation at −200 mV by ∼10-fold compared with 0 µM NS11021, while having little effect on the time course of activation. This action is most pronounced at negative voltages, at which the BK channel voltage sensors are at rest. Single-channel kinetic analysis further shows that 30 µM NS11021 increases open probability by 62-fold and increases mean open time from 0.15 to 0.52 ms in the nominal absence of Ca2+ at voltages less than −60 mV, conditions in which BK voltage sensors are largely in the resting state. We could therefore account for the major activating effects of NS11021 by a scheme in which the drug primarily shifts the pore-gate equilibrium toward the open state.

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“…The sensor for divalent cations is at the C-terminal region and is formed by two Regulator of Conductance for K + domains (RCK1 and RCK2) per α subunit (Wei et al, 1994; Moss and Magleby, 2001; Xia et al, 2002; Zeng et al, 2005; Wu et al, 2010). In the tetramer, four RCK1-RCK2 tandems pack against each other in a large structure known as the gating ring (Wu et al, 2010; Yuan et al, 2011; Giraldez and Rothberg, 2017; Tao et al, 2017; Zhou et al, 2017). Two high-affinity Ca 2+ binding sites are located in the RCK2 (also known as ‘Ca 2+ bowl’) and RCK1 domains, respectively.…”

Section: Introductionmentioning

confidence: 99%

Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor

Miranda

Holmgren

Giráldez

2018

eLife

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In humans, large conductance voltage- and calcium-dependent potassium (BK) channels are regulated allosterically by transmembrane voltage and intracellular Ca2+. Divalent cation binding sites reside within the gating ring formed by two Regulator of Conductance of Potassium (RCK) domains per subunit. Using patch-clamp fluorometry, we show that Ca2+ binding to the RCK1 domain triggers gating ring rearrangements that depend on transmembrane voltage. Because the gating ring is outside the electric field, this voltage sensitivity must originate from coupling to the voltage-dependent channel opening, the voltage sensor or both. Here we demonstrate that alterations of the voltage sensor, either by mutagenesis or regulation by auxiliary subunits, are paralleled by changes in the voltage dependence of the gating ring movements, whereas modifications of the relative open probability are not. These results strongly suggest that conformational changes of RCK1 domains are specifically coupled to the voltage sensor function during allosteric modulation of BK channels.

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Understanding the conformational motions of RCK gating rings

Abstract: A timely review of the structural basis of Ca2+-activated K+ channel modulation by regulator of conduction of K+ (RCK) domains

Cited by 21 publications

References 93 publications

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Molecular mechanism of BK channel activation by the smooth muscle relaxant NS11021

Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor

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