Beat-to-beat dynamic regulation of intracellular pH in cardiomyocytes
Yankun Lyu,
Phung N. Thai,
Lu Ren,
Valeriy Timofeyev,
Zhong Jian,
Seojin Park,
Kenneth S. Ginsburg,
James Overton,
Julie Bossuyt,
Donald M. Bers,
Ebenezer N. Yamoah,
Ye Chen-Izu,
Nipavan Chiamvimonvat,
Xiao-Dong Zhang
Affiliations
Yankun Lyu
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA
Phung N. Thai
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA
Lu Ren
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA
Valeriy Timofeyev
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA
Zhong Jian
Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA
Seojin Park
Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, NV 89557, USA
Kenneth S. Ginsburg
Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA
James Overton
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA
Julie Bossuyt
Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA
Donald M. Bers
Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA
Ebenezer N. Yamoah
Department of Physiology and Cell Biology, University of Nevada, Reno, Reno, NV 89557, USA
Ye Chen-Izu
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA; Department of Biomedical Engineering, University of California, Davis, Davis, CA 95616, USA
Nipavan Chiamvimonvat
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA; Department of Pharmacology, University of California, Davis, Davis, CA 95616, USA; Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655, USA
Xiao-Dong Zhang
Department of Internal Medicine, University of California, Davis, Davis, CA 95616, USA; Department of Veterans Affairs, Northern California Health Care System, Mather, CA 95655, USA; Corresponding author
Summary: The mammalian heart beats incessantly with rhythmic mechanical activities generating acids that need to be buffered to maintain a stable intracellular pH (pHi) for normal cardiac function. Even though spatial pHi non-uniformity in cardiomyocytes has been documented, it remains unknown how pHi is regulated to match the dynamic cardiac contractions. Here, we demonstrated beat-to-beat intracellular acidification, termed pHi transients, in synchrony with cardiomyocyte contractions. The pHi transients are regulated by pacing rate, Cl−/HCO3- transporters, pHi buffering capacity, and β-adrenergic signaling. Mitochondrial electron-transport chain inhibition attenuates the pHi transients, implicating mitochondrial activity in sculpting the pHi regulation. The pHi transients provide dynamic alterations of H+ transport required for ATP synthesis, and a decrease in pHi may serve as a negative feedback to cardiac contractions. Current findings dovetail with the prevailing three known dynamic systems, namely electrical, Ca2+, and mechanical systems, and may reveal broader features of pHi handling in excitable cells.
