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Endolysosomal calcium release and cardiac physiology.

Derek A Terrar1

  • 1Department of Pharmacology, Medical Sciences Division, University of Oxford, Mansfield Road, Oxford OX1 3QT, UK.

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Summary

Calcium ions regulate heart muscle pumping via endolysosomes and signaling molecules like NAADP. TPCs in endolysosomes control calcium release, impacting cardiac function in both health and disease.

Keywords:
CD38Calcium SignalingCardiac MyocyteCardiac atriaCardiac ventricleEndolysosomeHeartLysosomeMitochondriaNAADPSarcoplasmic Reticulum

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Area of Science:

  • Cardiovascular Physiology
  • Cellular Signaling
  • Molecular Cardiology

Background:

  • Calcium ions (Ca2+) are critical for cardiac excitation-contraction coupling, linking electrical activity to muscle contraction.
  • Endolysosomes, strategically located near sarcoplasmic reticulum (SR) and mitochondria in cardiac cells, participate in localized Ca2+ signaling within nanodomains.
  • Regulation of Ca2+ dynamics involves Ca2+ mobilizing agents and specific ion channels, influencing both normal physiology and pathological conditions.

Purpose of the Study:

  • To elucidate the roles of endolysosomes and their associated signaling pathways in cardiac excitation-contraction coupling.
  • To investigate the mechanisms of Ca2+ release from endolysosomes via two-pore domain channels (TPCs) and their regulation by nicotinic acid adenine dinucleotide phosphate (NAADP).
  • To differentiate the roles of TPC1 and TPC2 in normal cardiac function and in pathological states such as ischemia-reperfusion injury.

Main Methods:

  • Investigated Ca2+ signaling in mammalian cardiac cells focusing on endolysosome-organelle proximity.
  • Examined the function of TPC1 and TPC2 channels in mediating Ca2+ release from endolysosomes.
  • Studied the effects of NAADP and protein kinase A (PKA) on TPC activity and downstream signaling pathways.

Main Results:

  • Endolysosomes release Ca2+ via TPC1 (interacting with mitochondria) and TPC2 (influencing SR), enhanced by NAADP synthesized by CD38.
  • In normal physiology, NAADP-TPC2 signaling amplifies SR Ca2+ uptake via SERCA, increasing Ca2+ transient amplitude.
  • Pathologically, NAADP-TPC1 signaling to mitochondria during ischemia-reperfusion causes abnormal SR Ca2+ release and cardiac damage; PKA isoforms differentially regulate TPC1 and TPC2 pathways.

Conclusions:

  • Endolysosomes are key regulators of cardiac Ca2+ handling through TPC channels and NAADP signaling.
  • TPC1 and TPC2 mediate distinct Ca2+ signaling pathways with differential roles in cardiac health and disease.
  • Targeting endolysosomal Ca2+ signaling pathways offers potential therapeutic strategies for cardiovascular diseases.