title: Coupled Ca2+/H+ transport by cytoplasmic buffers regulates local Ca2+ and H+ ion signaling.
abstract: 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.
authors.affiliation: Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy, and Genetics, Oxford University, Oxford OX1 3PT, United Kingdom.
authors.forename: Pawel
authors.initials: P
authors.lastname: Swietach
authors.forename: Jae-Boum
authors.initials: JB
authors.lastname: Youm
authors.forename: Noriko
authors.initials: N
authors.lastname: Saegusa
authors.forename: Chae-Hun
authors.initials: CH
authors.lastname: Leem
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Spitzer
authors.forename: Richard D
authors.initials: RD
authors.lastname: Vaughan-Jones
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism*; D005470:Fluorometry; D006639:Histidine / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011522:Protons; D051381:Rats
chemical_list: D004151:Dipeptides; D011522:Protons; D006639:Histidine; D000255:Adenosine Triphosphate
keywords: calcium; dual microperfusion; heart; mobile buffer; pH