Hydrophobic interaction between contiguous residues in the S6 transmembrane segment acts as a stimuli integration node in the BK channel

Carrasquel-Ursulaez, Willy; Contreras, Gloria; Sepúlveda, Romina V.; Aguayo, Daniel; González-Nilo, Fernando D.; González, Carlos; Latorre, Ramón

doi:10.1085/jgp.201411194

Cited by 18 publications

(33 citation statements)

References 55 publications

(102 reference statements)

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“…Therefore, we started by examining the effects of extracellular acidification on the closed-open equilibrium in the BK pore region. To do this, we recorded BK single channel currents at negative potentials (−100, −120, −140 mV) where BK VSDs are largely in resting states even with elevated concentrations of [Ca 2+ ] in up to 100 μM ( Horrigan and Aldrich, 2002 ; Carrasquel-Ursulaez et al, 2015 ). A change in limiting open probability times the number of BK channels (limiting nP O ) determined from such recordings reflects a change in the C-O equilibrium of the BK pore gate ( Horrigan et al, 1999b ).…”

Section: Resultsmentioning

confidence: 99%

BK channel inhibition by strong extracellular acidification

Zhong

Xia

Lingle

2018

eLife

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Mammalian BK-type voltage- and Ca2+-dependent K+ channels are found in a wide range of cells and intracellular organelles. Among different loci, the composition of the extracellular microenvironment, including pH, may differ substantially. For example, it has been reported that BK channels are expressed in lysosomes with their extracellular side facing the strongly acidified lysosomal lumen (pH ~4.5). Here we show that BK activation is strongly and reversibly inhibited by extracellular H+, with its conductance-voltage relationship shifted by more than +100 mV at pHO 4. Our results reveal that this inhibition is mainly caused by H+ inhibition of BK voltage-sensor (VSD) activation through three acidic residues on the extracellular side of BK VSD. Given that these key residues (D133, D147, D153) are highly conserved among members in the voltage-dependent cation channel superfamily, the mechanism underlying BK inhibition by extracellular acidification might also be applicable to other members in the family.

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Section: Resultsmentioning

confidence: 99%

BK channel inhibition by strong extracellular acidification

Zhong

Xia

Lingle

2018

eLife

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“…Unlike in other K + channels, the Slo1 S6 segments may not function as the main ion conduction gate (27,28). However, select mutations of the residues therein dramatically alter voltage dependence of Slo1 activation (29)(30)(31)(32). For example, polar side chains at positions 312, 313, and 316 in S6 shifted the voltage dependence of activation to the negative direction, leading to the suggestion that the side chains at these positions experience different environments depending on the ion conduction gate status (31,32).…”

Section: Discussionmentioning

confidence: 99%

Atomic determinants of BK channel activation by polyunsaturated fatty acids

Tian

Aursnes

Hansen

et al. 2016

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

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Docosahexaenoic acid (DHA), a polyunsaturated ω-3 fatty acid enriched in oily fish, contributes to better health by affecting multiple targets. Large-conductance Ca 2+ -and voltage-gated Slo1 BK channels are directly activated by nanomolar levels of DHA. We investigated DHA-channel interaction by manipulating both the fatty acid structure and the channel composition through the site-directed incorporation of unnatural amino acids. Electrophysiological measurements show that the para-group of a Tyr residue near the ion conduction pathway has a critical role. To robustly activate the channel, ionization must occur readily by a fatty acid for a good efficacy, and a long nonpolar acyl tail with a Z double bond present at the halfway position for a high affinity. The results suggest that DHA and the channel form an ion-dipole bond to promote opening and demonstrate the channel druggability. DHA, a marine-derived nutraceutical, represents a promising lead compound for rational drug design and discovery. -4,7,10,13,16,19-hexaenoic acid], found abundantly in oily fish, are believed to have many health-promoting effects (1). For example, select ω-3 PUFAs may decrease cardiovascular disease risk (2). Furthermore, human studies suggest that ω-3 PUFAs may lower blood pressure in some individuals (3). Thus, PUFAs such as DHA are natural nutraceuticals with great potential as lead compounds for rational drug design and discovery. To be successful, such an effort requires clear mechanistic understanding of the interactions between PUFAs and their effectors (4); however, the molecular targets of PUFAs and the mechanisms of action are only beginning to be revealed.One of the high-affinity targets of PUFAs is the large-conductance Ca 2+ -and voltage-gated K + (Slo1 BK) channel (5), whose activation in vascular smooth muscle cells facilitates vessel relaxation (6). Vascular Slo1 BK channels made of four pore-forming Slo1 and auxiliary β1 subunits (Slo1 + β1) are potently and reversibly activated by DHA with a nanomolar level of EC 50 , and this effect contributes to the hypotensive action of DHA in wild-type mice but not in mice with the gene encoding the channel (KCNMA1) disrupted (5).The function of the Slo1 BK channel can be electrophysiologically monitored with high precision to produce quantitative results amenable to mechanistic interpretations (7,8). Such in vitro studies show that DHA biases the ion conduction gate of the channel toward the open conformation without any need for activation of the channel's Ca 2+ sensors in the intracellular domain or transmembrane voltage sensor domains (VSDs) (5). Structurally, the action of DHA depends on a Tyr residue [Y318 in human Slo1 (hSlo1)] near the intracellular end of the ion conduction pathway; the mutation Y318S abolishes the activating effect of DHA (9).The exact role of Y318 in mediating the effect of DHA, however, is not clear. Some clues may be gained from interactions of other proteins with PUFAs. Extracellular DHA regulates voltagegated K + channels by interacting with ...

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“…Therefore, maximum conductance, measured at saturating K + concentrations, is required to separate permeation from binding ( Díaz-Franulic et al, 2015 ; Sack and Tilley, 2015 ). In contrast, Phe380, located at the inner cavity of HSlo (F315 in MSlo), was shown to be critical for ion permeation when replacement with isoleucine or tyrosine decreased unitary conductance by ∼70% or ∼50%, respectively ( Carrasquel-Ursulaez et al, 2015 ). However, the impact of these mutations on the maximum conductance is unknown.…”

Section: Pore Architecture Of K + Channels: Implicmentioning

confidence: 99%

Pore size matters for potassium channel conductance

et al. 2016

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Ion channels are membrane proteins that mediate efficient ion transport across the hydrophobic core of cell membranes, an unlikely process in their absence. K+ channels discriminate K+ over cations with similar radii with extraordinary selectivity and display a wide diversity of ion transport rates, covering differences of two orders of magnitude in unitary conductance. The pore domains of large- and small-conductance K+ channels share a general architectural design comprising a conserved narrow selectivity filter, which forms intimate interactions with permeant ions, flanked by two wider vestibules toward the internal and external openings. In large-conductance K+ channels, the inner vestibule is wide, whereas in small-conductance channels it is narrow. Here we raise the idea that the physical dimensions of the hydrophobic internal vestibule limit ion transport in K+ channels, accounting for their diversity in unitary conductance.

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Hydrophobic interaction between contiguous residues in the S6 transmembrane segment acts as a stimuli integration node in the BK channel

Abstract: Phenylalanine 380 and leucine 377 in the BK channel S6 transmembrane helix of contiguous subunits participate in a hydrophobic interaction in both the closed and open state; this interaction is important in the allosteric coupling between the Ca2+ and voltage sensors and pore domain.

Cited by 18 publications

References 55 publications

BK channel inhibition by strong extracellular acidification

BK channel inhibition by strong extracellular acidification

Atomic determinants of BK channel activation by polyunsaturated fatty acids

Pore size matters for potassium channel conductance

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