Endolysosomal calcium release and cardiac physiology

Calcium ions play a central role in determining the timing and magnitude of the pumping action of heart muscle in a process which couples electrical activity of action potentials to muscle contraction. Regulation of this excitation-contraction coupling is achieved by Ca²⁺ signalling mechanisms that include activation of Ca²⁺ mobilising agents which influence the movement of Ca²⁺ between intracellular membrane-bound compartments. Research discussed here concerns endolysosomes, which play diverse signalling roles throughout the body. In the heart, a population of endolysosomes is strategically placed close to two other important membrane bound organelles, sarcoplasmic reticulum (SR) and mitochondria. In each case this proximity provides a structural basis for highly localised Ca²⁺ signalling in nanodomains between endolysosomes and the organelle. Ca²⁺ is released from endolysosomes via at least two varieties of two-pore domain channels (TPCs) in mammalian cardiac cells, TPC1 determining the interaction with mitochondria, while TPC2 controls the influence on SR. Ca²⁺ release via both TPC1 and TPC2 is enhanced by the Ca²⁺ mobilising agent, nicotinic acid adenine dinucleotide phosphate (NAADP) which is synthesised in the heart primarily by CD38. In normal physiology, NAADP plays an important regulatory role in which Ca²⁺ is released from endolysosomes via TPC2 channels into a nanodomain next to SR, and an amplification mechanism resulting from Ca²⁺ activation of CaMKII enhances SR Ca²⁺ uptake by the enzyme SERCA to increase the amplitude of the Ca²⁺ transient accompanying action potentials. A separate mechanism underlies pathology associated with reperfusion after ischaemia, when NAADP-mediated endolysosomal calcium release via TPC1 acts on nearby mitochondria resulting in abnormal SR Ca²⁺ release and extreme disruption to the normal excitation-contraction coupling process, causing muscle damage. There are different roles for PKA in the two pathways dependant on TPC1 or TPC2. Oxidising conditions during reperfusion following ischaemia promote disulphide bond formation in PKAIalpha causing accumulation of PKAI holoenzyme in endolysosomes and cardioprotective inhibition of TPC1 channels. In the case of TPC2, PKAII actions are thought to enhance NAADP synthesis by CD38 therefore promoting the endolysosomal influence on SR Ca²⁺. Excessive activation of this pathway leads to cardiac arrhythmias and hypertrophy.