Mechanism of modulation of the voltage-gated skeletal and cardiac muscle sodium channels by fatty acids

1997 ◽  
Vol 272 (2) ◽  
pp. C592-C600 ◽  
Author(s):  
S. Bendahhou ◽  
T. R. Cummins ◽  
W. S. Agnew
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Arachidonic Acid ◽  
Unsaturated Fatty Acids ◽  
Inactivation Kinetics ◽  
Na Channel ◽  
Na Channels ◽  
Channel Conductance ◽  
Na Current ◽  
Voltage Gated

Voltage-gated rat skeletal muscle and cardiac Na+ channels are modulated by exogenous unsaturated fatty acids. Application of 1-10 microM arachidonic or oleic acids reversibly depressed Na+ channel conductance and shifted the inactivation curve to hyperpolarizing potentials. These effects were not prevented by inhibitors of lipoxygenase, cyclooxygenase, cytochrome P-450 epoxygenase, or protein kinase C. Neither palmitic acid nor methyl ester oleate had an effect on the inward Na+ current, suggesting that trivial variations in membrane fluidity are not responsible for the Na+ current depression or kinetic changes. Arachidonic acid altered fast Na+ inactivation without changing the slow inactivation kinetics. Moreover, skeletal muscle Na+ channel gating currents were markedly decreased by 2 microM arachidonic acid. Finally, nonstationary noise analysis indicated that both the number of channels and the open probability were slightly decreased without change in the single-channel conductance. These data suggest that unsaturated fatty acids such as arachidonic and oleic acids 1) specifically regulate voltage-gated Na+ channels and 2) interact directly with Na+ channels, perhaps at a fatty acid binding domain, by decreasing the total gating charge and altering fast-inactivation kinetics.

scholarly journals Abnormal Na channel gating in murine cardiac myocytes deficient in myotonic dystrophy protein kinase

2003 ◽  
Vol 12 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Hwa C. Lee ◽  
Manoj K. Patel ◽  
Dilawaar J. Mistry ◽  
Qingcai Wang ◽  
Sita Reddy ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Current Density ◽  
Channel Gating ◽  
Resting Membrane Potential ◽  
Na Channel ◽  
Na Channels ◽  
Wild Type ◽  
Membrane Excitability ◽  
Na Current ◽  
Deficient Mice

DMPK is a serine/threonine kinase implicated in the human disease myotonic muscular dystrophy (DM). Skeletal muscle Na channels exhibit late reopenings in Dmpk-deficient mice and peak current density is reduced, implicating DMPK in regulation of membrane excitability. Since complete heart block and sudden cardiac death occur in the disease, we tested the hypothesis that cardiac Na channels also exhibit abnormal gating in Dmpk-deficient mice. We made whole cell and cell-attached patch clamp recordings of ventricular cardiomyocytes enzymatically isolated from wild-type, Dmpk+/−, and Dmpk−/− mice. Recordings from membrane patches containing one or a few Na channels revealed multiple Na channel reopenings occurring after the macroscopic Na current had subsided in both Dmpk+/− and Dmpk−/− muscle, but only rare reopenings in wild-type muscle (>3-fold difference, P < 0.05). This resulted in a plateau of non-inactivating Na current in Dmpk-deficient muscle. The magnitude of this plateau current was independent on the magnitude of the test potential from −40 to 0 mV and was also independent of gene dose. Macroscopic Na current density was similar in wild-type and Dmpk-deficient muscle, as was steady-state Na channel gating. Decay of macroscopic currents was slowed in Dmpk−/− muscle, but not in Dmpk+/− or wild-type muscle. Entry into, and recovery from, inactivation were similar at multiple test potentials in wild-type and Dmpk-deficient muscle. Resting membrane potential was depolarized, and action potential duration was significantly prolonged in Dmpk-deficient muscle. Thus in cardiac muscle, Dmpk deficiency results in multiple late reopenings of Na channels similar to those seen in Dmpk-deficient skeletal muscle. This is reflected in a plateau of non-inactivating macroscopic Na current and prolongation of cardiac action potentials.

scholarly journals Cardiac sodium channels (hH1) are intrinsically more sensitive to block by lidocaine than are skeletal muscle (mu 1) channels.

1995 ◽  
Vol 106 (6) ◽  
pp. 1193-1209 ◽  
Author(s):  
H B Nuss ◽  
G F Tomaselli ◽  
E Marbán
Keyword(s):  
Skeletal Muscle ◽  
Local Anesthetics ◽  
Time Course ◽  
Large Fraction ◽  
Expression System ◽  
Na Channel ◽  
Na Channels ◽  
Na Current ◽  
Unexpected Findings ◽  
Cardiac Sodium Channels

When lidocaine is given systemically, cardiac Na channels are blocked preferentially over those in skeletal muscle and nerve. This apparent increased affinity is commonly assumed to arise solely from the fact that cardiac Na channels spend a large fraction of their time in the inactivated state, which exhibits a high affinity for local anesthetics. The oocyte expression system was used to compare systematically the sensitivities of skeletal (mu 1-beta 1) and cardiac (hH1-beta 1) Na channels to block by lidocaine, under conditions in which the only difference was the choice of alpha subunit. To check for differences in tonic block, Na currents were elicited after 3 min of exposure to various lidocaine concentrations at -100 mV, a potential at which both hH1-beta 1 and mu 1-beta 1 channels were fully reprimed. Surprisingly, hH1-beta 1 Na channels were threefold more sensitive to rested-state block by lidocaine (402 +/- 36 microM, n = 4-22) than were mu 1-beta 1 Na channels (1,168 +/- 34 microM, n = 7-19). In contrast, the inactivated state binding affinities determined at partially depolarized holding potentials (h infinity approximately 0.2) were similar (Kd = 16 +/- 1 microM, n = 3-9 for hH1-beta 1 and 12 +/- 2 microM, n = 4-11 for mu 1-beta 1). Lidocaine produced more use-dependent block of peak hH1-beta 1 Na current elicited by trains of short-(10 ms) or long- (1 s) duration step depolarizations (0.5 Hz, -20 mV) than of mu 1-beta 1 Na current. During exposure to lidocaine, hH1-beta 1 channels recover from inactivation at -100 mV after a prolonged delay (20 ms), while mu 1-beta 1 channels begin repriming immediately. The overall time course of recovery from inactivation in the presence of lidocaine is much slower in hH1-beta 1 than in mu 1-beta 1 channels. These unexpected findings suggest that structural differences in the alpha subunits impart intrinsically different lidocaine sensitivities to the two isoforms. The differences in steady state affinities and in repriming kinetics are both in the correct direction to help explain the increased potency of cardiac Na channel block by local anesthetics.

scholarly journals Block of Tetrodotoxin-resistant Na+ Channel Pore by Multivalent Cations

2004 ◽  
Vol 124 (1) ◽  
pp. 27-42 ◽  
Author(s):  
Chung-Chin Kuo ◽  
Wan-Yu Chen ◽  
Ya-Chin Yang
Keyword(s):  
Conformational Changes ◽  
Selectivity Filter ◽  
Dorsal Root Ganglion Neurons ◽  
Inactivation Kinetics ◽  
Na Channel ◽  
Na Channels ◽  
Na Current ◽  
Single File ◽  
Pore Mouth ◽  
Ganglion Neurons

Tetrodotoxin-resistant (TTX-R) Na+ channels are much less susceptible to external TTX but more susceptible to external Cd2+ block than tetrodotoxin-sensitive (TTX-S) Na+ channels. Both TTX and Cd2+ seem to block the channel near the “DEKA” ring, which is probably part of a multi-ion single-file region adjacent to the external pore mouth and is involved in the selectivity filter of the channel. In this study we demonstrate that other multivalent transitional metal ions such as La3+, Zn2+, Ni2+, Co2+, and Mn2+ also block the TTX-R channels in dorsal root ganglion neurons. Just like Cd2+, the blocking effect has little intrinsic voltage dependence, but is profoundly influenced by Na+ flow. The apparent dissociation constants of the blocking ions are always significantly smaller in inward Na+ currents than those in outward Na+ current, signaling exit of the blocker along with the Na+ flow and a high internal energy barrier for “permeation” of these multivalent blocking ions through the pore. Most interestingly, the activation and especially the inactivation kinetics are slowed by the blocking ions. Moreover, the gating changes induced by the same concentration of a blocking ion are evidently different in different directions of Na+ current flow, but can always be correlated with the extent of pore block. Further quantitative analyses indicate that the apparent slowing of channel activation is chiefly ascribable to Na+ flow–dependent unblocking of the bound La3+ from the open Na+ channel, whereas channel inactivation cannot happen with any discernible speed in the La3+-blocked channel. Thus, the selectivity filter of Na+ channel is probably contiguous to a single-file multi-ion region at the external pore mouth, a region itself being nonselective in terms of significant binding of different multivalent cations. This region is “open” to the external solution even if the channel is “closed” (“deactivated”), but undergoes imperative conformational changes during the gating (especially the inactivation) process of the channel.

β-Subunit–Dependent Modulation of hSlo BK Current by Arachidonic Acid

2007 ◽  
Vol 97 (1) ◽  
pp. 62-69 ◽  
Author(s):  
X. Sun ◽  
D. Zhou ◽  
P. Zhang ◽  
E. G. Moczydlowski ◽  
G. G. Haddad
Keyword(s):  
Fatty Acids ◽  
Arachidonic Acid ◽  
Conformational Changes ◽  
Unsaturated Fatty Acids ◽  
Saturated Fatty Acids ◽  
Nordihydroguaiaretic Acid ◽  
Bk Channels ◽  
Bk Channel ◽  
Β Subunit ◽  
Α Subunit

In this study, we examined the effect of arachidonic acid (AA) on the BK α-subunit with or without β-subunits expressed in Xenopus oocytes. In excised patches, AA potentiated the hSlo-α current and slowed inactivation only when β2/3 subunit was co-expressed. The β2-subunit–dependent modulation by AA persisted in the presence of either superoxide dismutase or inhibitors of AA metabolism such as nordihydroguaiaretic acid and eicosatetraynoic acid, suggesting that AA acts directly rather than through its metabolites. Other cis unsaturated fatty acids (docosahexaenoic and oleic acid) also enhanced hSlo-α + β2 currents and slowed inactivation, whereas saturated fatty acids (palmitic, stearic, and caprylic acid) were without effect. Pretreatment with trypsin to remove the cytosolic inactivation domain largely occluded AA action. Intracellularly applied free synthetic β2-ball peptide induced inactivation of the hSlo-α current, and AA failed to enhance this current and slow the inactivation. These results suggest that AA removes inactivation by interacting, possibly through conformational changes, with β2 to prevent the inactivation ball from reaching its receptor. Our data reveal a novel mechanism of β-subunit–dependent modulation of BK channels by AA. In freshly dissociated mouse neocortical neurons, AA eliminated a transient component of whole cell K+ currents. BK channel inactivation may be a specific mechanism by which AA and other unsaturated fatty acids influence neuronal death/survival in neuropathological conditions.

scholarly journals Expression pattern of neuronal and skeletal muscle voltage-gated Na+channels in the developing mouse heart

2005 ◽  
Vol 564 (3) ◽  
pp. 683-696 ◽  
Author(s):  
Volker Haufe ◽  
Juan A. Camacho ◽  
Robert Dumaine ◽  
Bernd Günther ◽  
Christian Bollensdorff ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Expression Pattern ◽  
Mouse Heart ◽  
Na Channels ◽  
Voltage Gated

Altered sodium current response to intracellular fatty acids in halothane-hypersensitive skeletal muscle

1996 ◽  
Vol 271 (1) ◽  
pp. C347-C353 ◽  
Author(s):  
S. J. Wieland ◽  
Q. H. Gong ◽  
J. E. Fletcher ◽  
H. Rosenberg
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Sodium Current ◽  
Primary Cultures ◽  
Na Channel ◽  
Current Response ◽  
Whole Cell ◽  
Na Currents

Biopsies of human skeletal muscle were analyzed by an in vitro contracture test (IVCT) for responsiveness to a halothane challenge: noncontracting (nonresponsive; IVCT-) and contracting (IVCT+). A muscle biopsy that is IVCT+ indicates potential malignant hyperthermia (MH) susceptibility. Primary cultures were grown from portions of the skeletal muscle biopsies, and voltage-activated currents were measured by whole cell recording in the presence or absence of 2-5 microM intracellular arachidonic or oleic acids. In untreated IVCT- cells, Na+ currents were predominantly tetrodotoxin (TTX) insensitive, indicating that most of the current was carried through the embryonic SkM2 isoform of the Na+ channel. Inclusion of fatty acids in the recording pipette of IVCT- cells produced an increase in voltage-activated Na+ currents during 20 min of recording. Approximately 70% of currents in fatty acid-treated cells were TTX sensitive, indicating activation of the adult SkM1 isoform of the Na+ channel. In contrast to IVCT- cells, IVCT+ cells expressed Na+ currents that were predominantly TTX sensitive even in the absence of added fatty acid, thus showing a relatively large baseline functional expression of SkM1 channels. Addition of fatty acids to the recording pipette produced little further change in the magnitude or TTX sensitivity of the whole cell currents in IVCT+ cells, suggesting altered functional regulation of Na+ channels in MH muscle.

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