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  • chir99021 The IP R is a ubiquitously expressed Ca release ch


    The IP3R is a ubiquitously expressed Ca2+-release channel from the ER, activated by IP3, produced upon cellular stimulation by hormones, growth factors or neurotransmitters. Three genes are coding for the IP3R and their gene products (IP3R1, IP3R2, IP3R3) assemble in functional homo- or heterotetramers. The IP3Rs form large proteins of about 2700 a.a. in which 3 main regions are recognized: the N-terminal ligand-binding region, a large central regulatory and coupling region and the C-terminal region containing the 6 transmembrane domains [[134], [135], [136], [137], [138]]. The IP3Rs are regulated in a complex way by various cytosolic factors including Ca2+ and ATP, by various kinase-mediated phosphorylation processes [139] and by multiple associated proteins [131,140] including oncogenes and tumor suppressors involved in cellular life/death decisions [[141], [142], [143]]. The TPCs form a separate family of Ca2+ channels characterized by the presence of 12 transmembrane domains and expressed exclusively in acidic organelles. The TPC family contains 3 members, of which only two are expressed in humans: TPC1, expressed in the less acidic endosomes, and TPC2, expressed in late endosomes and lysosomes [144,145]. The third isoform, TPC3, has been conserved during evolution until the Mammalia in which in several lines it either disappeared (mouse and rat) or degenerated to pseudogenes (humans and other primates) [146]. It should be emphasized that while the IP3R is by far the major Ca2+-release channel of the ER in most cell types, lysosomes contain multiple Ca2+ channels such as e.g. the transient receptor potential (TRP) channels ML1–3 and M2 and the ionotropic purinergic receptor P2X4 [[147], [148], [149], [150]]. It is now generally accepted that not only phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) activates TPC2 but that this channel is also the physiological target of the secondary messenger nicotinic chir99021 adenine dinucleotide phosphate (NAADP) [144,[151], [152], [153], [154]]. The location of the NAADP-binding site however is still elusive and is probably located on an associated protein [153,155,156]. The various types of Ca2+ channels present in acidic organelles support their role as bona fide Ca2+ stores involved in Ca2+ signaling [147,149,[157], [158], [159]]. Moreover, it is important to observe that with respect to intracellular Ca2+ signaling, ER and lysosomes do not function independently, but that an important functional crosstalk exists between them [[160], [161], [162], [163]]. Consequently, Ca2+ release from both compartments, including by the IP3R and the TPC2, have already been involved in autophagy [107,118]. Ca2+ signals function as important modulators of the autophagy process and the Ca2+ sensor CaM can control various autophagy effectors. Moreover, all cellular organelles can contribute in an interconnected way to those Ca2+ signals and both the ER-located IP3R and the lysosomal TPC2 channel participate to this signaling. Interestingly, CaM, the IP3R and the TPC2 channel are all three ubiquitously expressed, supporting an important and general role for their function.
    Conclusions The data presented in this review indicate that the ROCO kinases and the related DAPK2 play a role in the autophagy process, and that at several levels there exist a crosstalk exist between their action and Ca2+ signaling. A marked difference exist here between LRRK2 acting upstream of Ca2+ signaling by eliciting them and the DAPK1 and 2 that act downstream of existing Ca2+ signals. Further research will therefore be needed to unravel the complex roles of the various ROCO kinases in autophagy, their exact link to Ca2+ signaling and their functional and/or structural interrelations. One of the points thereby to be elucidated is whether and how LRRK2/DAPK1 heterodimers relate to intracellular Ca2+ signals in the modulation of autophagy. Such knowledge is anticipated to be important for the further development of novel therapeutic strategies against neurodegenerative disorders, cancer and auto-immune diseases.