Na/Ca Exchange and Na/K-ATPase Function Are Equally Concentrated in Transverse Tubules of Rat Ventricular Myocytes

Despa, Sanda; Brette, Fabien; Orchard, Clive H.; Bers, Donald M.

doi:10.1016/s0006-3495(03)74758-4

Cited by 123 publications

(129 citation statements)

References 27 publications

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“…This reduction in the elevation of [Ca 2ϩ ] r supports the idea that NCX activity in MHN and MHS muscle fiber appears to be predominantly across the t-tubule rather than the surface sarcolemma. These results agree with previous studies showing that localization of NCX is higher in the t-tubular system than in the sarcolemma in skeletal and cardiac muscles (6,55 ] r must be considered with caution due to the lack of selectivity of KB-R7943, because there are evidences that show that it also inhibits voltage-gated Na ϩ and Ca 2ϩ channels, the inward rectifying K ϩ channels in cardiac cells (56), the transient receptor potential channels (TRPCs) in HEK293 cells (57), and RyR1 in skeletal muscle and HEK293 cells (58).…”

Section: Discussionsupporting

confidence: 93%

Ca2+ Influx via the Na+/Ca2+ Exchanger Is Enhanced in Malignant Hyperthermia Skeletal Muscle

Altamirano

Eltit

Robin

et al. 2014

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 93%

Ca2+ Influx via the Na+/Ca2+ Exchanger Is Enhanced in Malignant Hyperthermia Skeletal Muscle

Altamirano

Eltit

Robin

et al. 2014

Journal of Biological Chemistry

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“…20 Using this technique, we have shown previously that I Ca , Na-Ca 2ϩ exchange, and Na-K pump currents are located predominantly in the t-tubules. 18,24 In the present study, we found that total I Na is evenly distributed between surface sarcolemma and the t-tubules, in accordance with our previous work. 27 Recording I Na is prone to voltage clamp errors.…”

supporting

confidence: 93%

No Apparent Requirement for Neuronal Sodium Channels in Excitation-Contraction Coupling in Rat Ventricular Myocytes

Brette

Orchard

2006

Circulation Research

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Abstract-The majority of Na channels in the heart are composed of the tetrodotoxin (TTX)-resistant (K D , 2 to 6 mol/L) "cardiac" Na V 1.5 isoform; however, TTX-sensitive (K D , 1 to 25 nmol/L) "neuronal" Na channel isoforms have recently been detected in several cardiac preparations. In the present study, we determined the functional subcellular localization of Na channel isoforms (according to their TTX sensitivity) in rat ventricular myocytes by recording I Na in control and detubulated myocytes. We found that TTX-sensitive I Na (K D , Ϸ8.8 nmol/L) makes up 14Ϯ3% of total I Na in control and Յ4% in detubulated myocytes and calculated that Ϸ80% of TTX-sensitive I Na is located in the t-tubules, where it generates Ϸ1/3 of t-tubular I Na . In contrast, TTX-resistant I Na is located predominantly (Ϸ78%) at the surface membrane. We also investigated the possible contribution of TTX-sensitive I Na to excitation-contraction coupling, using 200 nmol/L TTX to selectively block TTX-sensitive I Na . TTX decreased the rate of depolarization of the action potential by 10% but did not delay the rise of systolic Ca 2ϩ in the center of the cell (transverse confocal line scan), suggesting that TTX-sensitive I Na does not play a role in synchronizing Ca 2ϩ release at the t-tubules; the amplitude of the Ca 2ϩ transient and contraction were also unchanged by 200 nmol/L TTX. The quantity of charge entering via I Ca elicited by control or TTX action potential waveforms was similar, suggesting that the trigger for Ca 2ϩ release is not altered by blocking TTX-sensitive I Na . We conclude that neuronal I Na is concentrated at the t-tubules, but there is no evidence of a requirement for these channels in normal excitation-contraction coupling in ventricular myocytes. (Circ Res. 2006;98:667-674.)Key Words: cardiac myocytes Ⅲ sodium channels Ⅲ excitation-contraction coupling Ⅲ electrophysiology I n mammalian cardiac muscle, release of Ca 2ϩ from the sarcoplasmic reticulum (SR) is the key event linking membrane depolarization and mechanical activity during excitation-contraction (EC) coupling. 1 Ca 2ϩ influx via L-type Ca 2ϩ channels is the major source of trigger Ca 2ϩ , which activates ryanodine receptors in the membrane of the adjacent SR by a process known as Ca 2ϩ -induced Ca 2ϩ release. 2 Ca 2ϩ -induced Ca 2ϩ release may also be triggered by Ca 2ϩ entry via reverse Na-Ca 2ϩ exchange, albeit with lower efficacy. 3 Voltage-gated Na channels play an important role in EC coupling by causing the rapid upstroke of the action potential and the propagation of excitation from cell to cell. 1 Ten genes encoding the ␣ (pore-forming) subunit of the Na channel have been cloned from different mammalian tissues. 4 Until recently, it appeared that the main pore-forming subunit in mammalian cardiac tissue was the Na V 1.5 isoform. 1 However, although Na V 1.5 is highly expressed at the mRNA level in the mammalian heart, other ␣ subunit isoforms have also been detected (Na V 1.1, Na V 1.2, Na V 1.3, Na V 1.4, Na V 1.6, collectively called neuron...

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“…Combined with the t-tubule area/volume ratio of Soeller and Cannell (1999), this provides a t-tubule fraction of 52%. Interestingly, detubulation of ventricular cells from Sprague Dawley rats results in similar losses of cell capacitance (32%; Despa et al 2003) as in the Wistar rats used in the present study.…”

Section: Effect Of Cholesterol On Membrane Capacitancesupporting

confidence: 73%

“…Membrane capacitance is a function of membrane area, and decreases by ~32% after detubulation Brette et al, 2004a;Brette et al, 2004b;Brette & Orchard, 2006a;Despa et al, 2003;Kawai et al, 1999;Komukai et al, 2002;Yang et al, 2002). This is similar to the fraction of cell membrane estimated to be in the ttubules using electron microscopy (Page, 1978).…”

Section: Which Estimate Of T-tubule Membrane Area Is Correct?supporting

confidence: 62%

Quantification of t-tubule area and protein distribution in rat cardiac ventricular myocytes

Pásek

Brette

Nelson

et al. 2008

Progress in Biophysics and Molecular Biology

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The transverse (t-) tubules of cardiac ventricular myocytes are invaginations of the surface membrane that form a complex network within the cell. Many of the key proteins involved in excitation-contraction coupling appear to be located predominantly at the t-tubule membrane.Despite their importance, the fraction of cell membrane within the t-tubules remains unclear: measurement of cell capacitance following detubulation suggests ~32%, whereas optical measurements suggest up to ~65%. We have therefore investigated the factors that may account for this discrepancy. Calculation of the combinations of t-tubule radius, length and density that produce t-tubular membrane fractions of 32% or 56% suggest that the true fraction is at the upper end of this range. Assessment of detubulation using confocal and electron microscopy suggests that incomplete detubulation can account for some, but not all of the difference. High cholesterol, and a consequent decrease in specific capacitance, in the t-tubule membrane, may also cause the ttubule fraction calculated from the loss of capacitance following detubulation to be underestimated. Correcting for both of these factors results in an estimate that is still lower than that obtained from optical measurements suggesting either that optical methods overestimate the fraction of membrane in the t-tubules, or that other, unknown, factors, reduce the apparent fraction obtained by detubulation. A biophysically realistic computer model of a rat ventricular myocyte, incorporating a t-tubule network, is used to assess the effect of the altered estimates of t-tubular membrane fraction on the calculated distribution of ion flux pathways.

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Na/Ca Exchange and Na/K-ATPase Function Are Equally Concentrated in Transverse Tubules of Rat Ventricular Myocytes

Cited by 123 publications

References 27 publications

Ca2+ Influx via the Na+/Ca2+ Exchanger Is Enhanced in Malignant Hyperthermia Skeletal Muscle

Ca2+ Influx via the Na+/Ca2+ Exchanger Is Enhanced in Malignant Hyperthermia Skeletal Muscle

No Apparent Requirement for Neuronal Sodium Channels in Excitation-Contraction Coupling in Rat Ventricular Myocytes

Quantification of t-tubule area and protein distribution in rat cardiac ventricular myocytes

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