Coupled Ca2+/H+ transport by cytoplasmic buffers regulates local Ca2+ and H+ ion signaling

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 22; pp. E2064 - E2073
• Main Authors: Swietach, Pawel, Youm, Jae-Boum, Saegusa, Noriko, Leem, Chae-Hun, Spitzer, Kenneth W, Vaughan-Jones, Richard D
• Format: Journal Article
• Language: English
• Published: United States National Acad Sciences 28.05.2013; National Academy of Sciences
• Series: PNAS Plus
• Subjects: acetates; adenosine triphosphate; Adenosine Triphosphate - metabolism; Animals; Biological Sciences; buffers; calcium; Calcium Signaling - physiology; cardiomyocytes; carnosine; Cytoplasm - metabolism; Dipeptides - metabolism; fluorescence; Fluorometry; glycolysis; Histidine - metabolism; image analysis; ion exchange; ions; magnesium; Microscopy, Fluorescence; mitochondria; Myocytes, Cardiac - metabolism; PNAS Plus; proteins; Protons; Rats; sarcoplasmic reticulum; pH; dual microperfusion; mobile buffer; calcium; heart
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1222433110

Ca(2+) signaling regulates cell function. This is subject to modulation by H(+) ions that are universal end-products of metabolism. Due to slow diffusion and common buffers, changes in cytoplasmic [Ca(2+)] ([Ca(2+)]i) or [H(+)] ([H(+)]i) can become compartmentalized, leading potentially to complex spatial Ca(2+)/H(+) coupling. This was studied by fluorescence imaging of cardiac myocytes. An increase in [H(+)]i, produced by superfusion of acetate (salt of membrane-permeant weak acid), evoked a [Ca(2+)]i rise, independent of sarcolemmal Ca(2+) influx or release from mitochondria, sarcoplasmic reticulum, or acidic stores. Photolytic H(+) uncaging from 2-nitrobenzaldehyde also raised [Ca(2+)]i, and the yield was reduced following inhibition of glycolysis or mitochondrial respiration. H(+) uncaging into buffer mixtures in vitro demonstrated that Ca(2+) unloading from proteins, histidyl dipeptides (HDPs; e.g., carnosine), and ATP can underlie the H(+)-evoked [Ca(2+)]i rise. Raising [H(+)]i tonically at one end of a myocyte evoked a local [Ca(2+)]i rise in the acidic microdomain, which did not dissipate. The result is consistent with uphill Ca(2+) transport into the acidic zone via Ca(2+)/H(+) exchange on diffusible HDPs and ATP molecules, energized by the [H(+)]i gradient. Ca(2+) recruitment to a localized acid microdomain was greatly reduced during intracellular Mg(2+) overload or by ATP depletion, maneuvers that reduce the Ca(2+)-carrying capacity of HDPs. Cytoplasmic HDPs and ATP underlie spatial Ca(2+)/H(+) coupling in the cardiac myocyte by providing ion exchange and transport on common buffer sites. Given the abundance of cellular HDPs and ATP, spatial Ca(2+)/H(+) coupling is likely to be of general importance in cell signaling.