Pairing phosphoinositides with calcium ions in endolysosomal dynamics

Abstract

The direction and specificity of endolysosomal membrane trafficking is tightly regulated by various cytosolic and membrane-bound factors, including soluble NSF attachment protein receptors (SNAREs), Rab GTPases, and phosphoinositides. Another trafficking regulatory factor is juxtaorganellar Ca2+, which is hypothesized to be released from the lumen of endolysosomes and to be present at higher concentrations near fusion/fission sites. The recent identification and characterization of several Ca2+ channel proteins from endolysosomal membranes has provided a unique opportunity to examine the roles of Ca2+ and Ca2+ channels in the membrane trafficking of endolysosomes. SNAREs, Rab GTPases, and phosphoinositides have been reported to regulate plasma membrane ion channels, thereby suggesting that these trafficking regulators may also modulate endolysosomal dynamics by controlling Ca2+ flux across endolysosomal membranes. In this review, we will discuss about the roles of phosphoinositides, Ca2+, and potential interactions between endolysosomal Ca2+ channels and phosphoinositides in endolysosomal dynamics.

Lysosomal Physiology

“…The permeation and gating properties of TRPML1 suggest that the channel function of TRPML1 is to release Ca 2+ from the LEL lumen in response to various cellular cues (83, 98), such as an increase in lysosomal PI(3,5)P 2 . TRPML1 may regulate the LE maturation process involving LE-lysosome fusion, as the lysosomal delivery of endocytosed proteins, such as plasma membrane growth factor receptors, is delayed in Trpml1 −/− cells (99, 100).…”

Congenital Myopathies: An Update

“…Phosphoinositides and their regulatory enzymes are primarily involved in the trafficking of membranes and vesicles between subcellular organelle membranes [68]. …”

A New Perspective of Lysosomal Cation Channel-Dependent Homeostasis in Alzheimer’s Disease

“…The source of the unidentified Ca 2+ channels from the lumen of acidic organelles and vesicles [46], that can mediate Ca 2+ release is the ML1 [4,5,34]. Though considering how difficult it may be to clamp intracellular Ca 2+ , a perfectly firm condition to rule out the participation of Ca 2+ from the lysosomal Ca 2+ stores may have not been adequately ensured in the [20] documentation.…”

“…A stringent requirement for a functional luminal acid hydrolases is low pH L, of 4.5 to 5.0, maintained by ATP-mediated proton pump and leak hypothesis. Either pump in or leak out of H + is electrogenic requiring a counter mechanism (ML1/TPC2-mediated cation efflux or anion influx that may not be the rheogenic Cl _ antiporter) to banish a positive net charge inside the lumen generated by ATP hydrolysis to regulate V-ATPase, the principle regulator of pH L in membrane trafficking, accumulation of macromolecules and altered Ca 2+ homeostasis are common typical features in NP form of LSD [4,5,20,34]. For the AD and as observed in Fig.…”