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Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons

Abstract

Lactic acid produced by anaerobic metabolism during cardiac ischemia is among several compounds suggested to trigger anginal chest pain1,2; however, the pH reached when a coronary artery is occluded (pH 7.0 to 6.7)3,4 can also occur during systemic acidosis, which causes no chest pain. Here we show that lactate, acting through extracellular divalent ions, dramatically increases activity of an acid-sensing ion channel (ASIC) that is highly expressed on sensory neurons that innervate the heart5,6. The effect should confer upon neurons that express ASICs an extra sensitivity to the lactic acidosis of local ischemia compared to acidity caused by systemic pathology.

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Figure 1: Lactate enhances ASICs.
Figure 2: Lactate modifies the medium, not the channel.

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Acknowledgements

We thank R. Waldmann and M. Lazdunski for providing clones, M. Bobo for tissue culture, and S. Sutherland, J. Adelman, S. Cook and C. Benson for comments. The NIH supported this work.

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Correspondence to D. C. Immke or E. W. McCleskey.

Supplementary information

Supplementary Fig. 1.

Lactate works without a signaling cascade. (a) Currents from an excised outside-out patch are enhanced by lactate. (b) Lactate effect is complete within the time of a solution exchange (20 ms). Four successive pH 7 stimuli applied 30 s apart with lactate addition as indicated. Lactate enhances current only if it is applied with the stimulating solution and there is no effect due to a 30-s preincubation. Solution changes take 20 ms or less, so lactate action and reversal must be faster than this, arguing against a mechanism requiring a signaling cascade between lactate and the channel. (JPG 65 kb)

Supplementary Fig. 2.

Other monocarboxylates modulate ASICs. A representative cell (left) and the average (&177;s.e.m.) percent increase in pH 7-evoked current by 15 mM lactate, 15 mM pyruvate and 15 mM formate. Each monocarboxylate enhances current, but their order of efficacy is lactate > pyruvate > formate. n = 4 cells. (JPG 61 kb)

Supplementary Fig. 3.

Divalent ions mimic lactate. Average (&177; s.e.m.) percent increase in pH 7-evoked current caused by 3 concentrations of lactate in 2 and 1 mM total Ca2+ and Mg2+ concentrations (solid bars) compared to the increase in lactate-free solutions containing the Ca2+ and Mg2+ concentrations calculated to be free in the respective lactate solutions (hatched bars). n = 4-15 cells. (JPG 63 kb)

Supplementary Fig. 4.

Both Ca2+ and Mg2+ affect gating. Currents from a cell stimulated with pH 7.0 at three different divalent ion concentrations. Current increases when either Mg or Ca drops. (JPG 60 kb)

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Immke, D., McCleskey, E. Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci 4, 869–870 (2001). https://doi.org/10.1038/nn0901-869

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