Membrane Stiffness and Channel Function

Lundbæk, Jens August; Birn, P.; Girshman, Jeffrey; Hansen, and A. J.; Andersen, Olaf S.

doi:10.1021/bi952250b

Cited by 271 publications

(283 citation statements)

References 39 publications

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“…As the energy required for the translational motion of molecules represent an important contribution of the total potential energy of the system, this observation means that protein conformational changes will occur more easily, according to the physical law relating the free energy difference between different protein conformations and changes in the bilayer deformation energy. 27 Then, the conclusion drawn from NMR investigations of total mitochondrial water and its structured fraction is that HAM and HCM with an opened PTP share in common a reduction of the matrix viscosity, acceleration of water dynamics and temperature dependency of its translational motion, but differ in the relative amount of structured water and physical behavior of its rotational motion. On the other hand, HCM incubated in vitro with Bax a share in common a comparable level of the structured water fraction and the absence of significant change in T1obs.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial membrane permeabilization produced by PTP, Bax and apoptosis: a 1H-NMR relaxation study

et al. 2005

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To analyze the involvement of structured water (bound to macromolecules) in apoptosis-induced mitochondrial outermembrane permeability, we compared the dynamics of water protons from nuclear magnetic resonance (NMR) data in apoptotic liver mitochondria with that of control mitochondria incubated in vitro with free Ca 2 þ (opening of the permeability transition pore, PTP) or with Bax a. Our results demonstrate that water molecules in apoptotic mitochondria exhibit an accelerated translational motion of structured water common with that induced by the opening of the PTP, but limited in amplitude. On the other hand, no significant quantitative change in structured water was observed in apoptotic mitochondria, a phenomenon also observed with Bax ainduced permeability. We conclude that the changes observed in the different water phases differ both quantitatively and qualitatively during the opening of the PTP and the Bax a-induced permeability, and that the apoptotic mitochondria exhibit mixed properties between these model situations.

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Section: Discussionmentioning

confidence: 99%

Mitochondrial membrane permeabilization produced by PTP, Bax and apoptosis: a 1H-NMR relaxation study

et al. 2005

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“…However, Andersen and associates (24,25) recently carefully examined experiments and clearly reproposed an alternative paradigm that ligands may act by primarily affecting the phospholipid bilayer surrounding the transmembrane ion channels in a way that secondarily affects stresses on the ion channels causing changes in their conformation, which then alter the conductance of the channels. It seems that this alternative paradigm might equally be consistent with our results.…”

Section: Discussionmentioning

confidence: 99%

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels

Xiao

Ke²,

Wang³

et al. 2001

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

115

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Suppression of cardiac voltage-gated Na ؉ currents is probably one of the important factors for the cardioprotective effects of the n-3 polyunsaturated fatty acids (PUFAs) against lethal arrhythmias. The ␣ subunit of the human cardiac Na ؉ channel (hH1␣) and its mutants were expressed in human embryonic kidney (HEK293t) cells. The effects of single amino acid point mutations on fatty acid-induced inhibition of the hH1 ␣ Na ؉ current (INa) were assessed. Eicosapentaenoic acid (EPA, C20:5n-3) significantly reduced I Na in HEK293t cells expressing the wild type, Y1767K, and F1760K of hH1␣ Na ؉ channels. The inhibition was voltage and concentration-dependent with a significant hyperpolarizing shift of the steady state of INa. In contrast, the mutant N406K was significantly less sensitive to the inhibitory effect of EPA. The values of the shift at 1, 5, and 10 M EPA were significantly smaller for N406K than for the wild type. Coexpression of the ␤1 subunit and N406K further decreased the inhibitory effects of EPA on I Na in HEK293t cells. In addition, EPA produced a smaller hyperpolarizing shift of the V1/2 of the steady-state inactivation in HEK293t cells coexpressing the ␤1 subunit and N406K. These results demonstrate that substitution of asparagine with lysine at the site of 406 in the domain-1-segment-6 region (D1-S6) significantly decreased the inhibitory effect of PUFAs on I Na, and coexpression with ␤1 decreased this effect even more. Therefore, asparagine at the 406 site in hH1␣ may be important for the inhibition by the PUFAs of cardiac voltage-gated Na ؉ currents, which play a significant role in the antiarrhythmic actions of PUFAs.human cardiac Na ϩ channel ͉ ␤1 subunit ͉ polyunsaturated fatty acids

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“…In contrast, epithelial Na ϩ channels and TrpC channels were shown to be inhibited by cholesterol depletion (8,9). In general, 3 basic mechanisms have been proposed: (i) specific interaction of a channel protein with cholesterol as a boundary lipid (10,11), (ii) hydrophobic mismatch between the channel and the lipid core of the membrane (12,13), and (iii) indirect effects through the interactions of ion channels with regulatory lipids or proteins within the environment of cholesterol-rich membrane domains (1,14,15). The structural basis of the sensitivity of ion channels to cholesterol, however, is unknown.…”

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confidence: 99%

Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol

Epshtein

Chopra

Rosenhouse‐Dantsker

et al. 2009

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

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A variety of ion channels are regulated by cholesterol, a major lipid component of the plasma membrane whose excess is associated with multiple pathological conditions. However, the mechanism underlying cholesterol sensitivity of ion channels is unknown. We have recently shown that an increase in membrane cholesterol suppresses inwardly rectifying K ؉ (Kir2) channels that are responsible for maintaining membrane potential in a variety of cell types. Here we show that cholesterol sensitivity of Kir2 channels depends on a specific region of the C terminus of the cytosolic domain of the channel, the CD loop. Within this loop, the L222I mutation in Kir2.1 abrogates the sensitivity of the channel to cholesterol whereas a reverse mutation in the corresponding position in Kir2.3, I214L, has the opposite effect, increasing cholesterol sensitivity. Furthermore, the L222I mutation has a dominant negative effect on cholesterol sensitivity of Kir2.1 WT. Mutations of 2 additional residues in the CD loop in Kir2.1, N216D and K219Q, partially affect the sensitivity of the channel to cholesterol. Yet, whereas these mutations have been shown to affect activation of the channel by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2], other mutations outside the CD loop that have been previously shown to affect activation of the channel by PI(4,5)P2 had no effect on cholesterol sensitivity. Mutations of the lipid-facing residues of the outer transmembrane helix also had no effect. These findings provide insights into the structural determinants of the sensitivity of Kir2 channels to cholesterol, and introduce the critical role of the cytosolic domain in cholesterol dependent channel regulation.

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Membrane Stiffness and Channel Function

Cited by 271 publications

References 39 publications

Mitochondrial membrane permeabilization produced by PTP, Bax and apoptosis: a 1H-NMR relaxation study

Mitochondrial membrane permeabilization produced by PTP, Bax and apoptosis: a 1H-NMR relaxation study

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels

Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol

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Membrane Stiffness and Channel Function

Cited by 271 publications

References 39 publications

Mitochondrial membrane permeabilization produced by PTP, Bax and apoptosis: a 1H-NMR relaxation study

Mitochondrial membrane permeabilization produced by PTP, Bax and apoptosis: a 1H-NMR relaxation study

Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na + channels

Identification of a C-terminus domain critical for the sensitivity of Kir2.1 to cholesterol

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Single point mutations affect fatty acid block of human myocardial sodium channel α subunit Na ⁺ channels