Na+ ions as spatial intracellular messengers for co-ordinating Ca2+ signals during pH heterogeneity in cardiomyocytes. (16th December 2014)

• Record Type: Journal Article
• Authors: Swietach, Pawel; Spitzer, Kenneth W.; Vaughan-Jones, Richard D.
• Is Part Of: Cardiovascular research. Volume 105:Number 2(2015)
• Page Start: 171
• Page End: 181
• Publication Date: 2014-12-16
• Subjects: Acidosis -- Calcium -- Diffusion -- E–C coupling -- Na+–H+ exchange; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvu251
• Languages: English
• ISSNs: 0008-6363

Abstract

Abstract: Aims: Contraction of the heart is regulated by electrically evoked Ca 2+ transients (CaTs). H + ions, the end products of metabolism, modulate CaTs through direct interactions with Ca 2+ -handling proteins and via Na + -mediated coupling between acid-extruding proteins (e.g. Na + /H + exchange, NHE1) and Na + /Ca 2+ exchange. Restricted H + diffusivity in cytoplasm predisposes pH-sensitive Ca 2+ signalling to becoming non-uniform, but the involvement of readily diffusible intracellular Na + ions may provide a means for combatting this. Methods and results: CaTs were imaged in fluo3-loaded rat ventricular myocytes paced at 2 Hz. Cytoplasmic [Na + ] ([Na + ]i ) was imaged using SBFI. Intracellular acidification by acetate exposure raised diastolic and systolic [Ca 2+ ] (also observed with acid-loading by ammonium prepulse or CO2 exposure). The systolic [Ca 2+ ] response correlated with a rise in [Na + ]i and sarcoplasmic reticulum Ca 2+ load, and was blocked by the NHE1 inhibitor cariporide (CO2 /HCO3 − -free media). Exposure of one half of a myocyte to acetate using dual microperfusion (CO2 /HCO3 − -free media) raised diastolic [Ca 2+ ] locally in the acidified region. Systolic [Ca 2+ ] and CaT amplitude increased more uniformly along the length of the cell, but only when NHE1 was functional. Cytoplasmic Na + diffusivity ( D Na ) was measured in quiescent cells, with strophanthidin present to inhibit the Na + /K + pump. With regional acetate exposure to activate a local NHE-driven Na + -influx, D Na was found to be sufficiently fast (680 µm 2 /s) for transmitting the pH–systolic Ca 2+ interaction over long distances. Conclusions: Na + ions are rapidly diffusible messengers that expand the spatial scale of cytoplasmic pH–CaT interactions, helping to co-ordinate global Ca 2+ signalling during conditions of intracellular pH non-uniformity.