Investigation of the role of TRPML channel family and two-pore channel family members in intracellular fusion processes and the cation homeostasis of endolysosomal vesicles

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Cation homeostasis and pH regulation are essential for the function of endosomes, lysosomes and lysosome-related organelles (LROs) such as melanosomes. Although it has been known for a while how acidification of lysosomes and LROs is achieved, i.e. primarily via ATP-driven proton pumps (vacuolar H+-ATPases), still relatively little is known about the fine regulation of luminal pH in endosomes, lysosomes, melanosomes, or other LROs as well as the regulation of intraluminal cation concentrations such as calcium, sodium and potassium, but also heavy metals such as iron, zinc, copper for example. Further unclear is how the different endolysosomal fusion processes are regulated and how the calcium that appears to be necessary for most of such fusion processes is provided. Members of the TRP (transient receptor potential) family of non-selective cation channels, in particular the mucolipins TRPML1-3 as well as the two-pore channels (TPCs), TPC1 and TPC2, are preferentially expressed in the endolysosomal system and are likely to play decisive roles in the regulation of the above mentioned processes. By analyzing knock-out mouse models as well as protein-protein interactions the physiological role and function of TRPML channels and TPCs in such processes shall be investigated.