The intracellular Ca²⁺channels of membrane traffic

Abstract

The exquisite timing of neurotransmitter release is a key determinant of neuronal function. It is an excellent example of a signal-centric paradigm involving interpretation and amplification of an incoming signal. As in all signaling systems, amplification in this model improves fidelity and timing of signaling. The Ca 2+ -dependence of synaptic vesicle release is a necessary requirement for translating action potentials into a release of neuromediators. The flooding of SNARE docking complexes by Ca 2+ entering the cell through voltage-gated Ca 2+ channels, followed by conformational changes that ultimately drive membrane fusion, is responsible for the incredibly robust and rapid neurotransmitter release in response to electrical stimulation.1 This signal-interpretation-response paradigm however remains largely unresolved in critical cellular processes involving other intracellular membrane organelles such as endosomes and lysosomes. However, several recent developments, primarily stemming from identification and characterization of new Regulation of organellar fusion and fission by Ca 2+ has emerged as a central paradigm in intracellular membrane traffic. Originally formulated for Ca 2+ -driven SNARE-mediated exocytosis in the presynaptic terminals, it was later expanded to explain membrane traffic in other exocytic events within the endo-lysosomal system. The list of processes and conditions that depend on the intracellular membrane traffic includes aging, antigen and lipid processing, growth factor signaling and enzyme secretion. Characterization of the ion channels that regulate intracellular membrane fusion and fission promises novel pharmacological approaches in these processes when their function becomes aberrant. The recent identification of Ca 2+ permeability through the intracellular ion channels comprising the mucolipin (TRPMLs) and the twopore channels (TPCs) families pinpoints the candidates for the Ca 2+ channel that drive intracellular membrane traffic. The present review summarizes the recent developments and the current questions relevant to this topic.

Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein

“…Interestingly, NPC cells have defective Ca 2ϩ mobilization from lysosomes (39) associated with impaired trafficking and metabolism of cholesterol in endolysosomal compartments. This deficit could be partially restored by elevating the cytosolic Ca 2ϩ concentration (55). Of interest, NPC cells, as well as other models of lysosomal storage disorders, also show accumulation of APP and CTFs (9, 36, 56 -59) similar to the S1P-lyase KO.…”

Tobacco Smoke Constituents Trigger Cytoplasmic Calcium Release

“…10 While we do not know the efflux pathway present in lysosomes, two pore channels and transient receptor potential cation channels (TRPMLs) are candidate Ca 2+ channels that may have been activated by tobacco smoke to trigger lysosomal Ca 2+ release. [23][24][25] Prolonged elevation of Ca 2+ is associated with stress responses and a transition to an apoptotic state, regardless of whether the cells actually undergo cell death or not. 26 Thus, beyond the effects that we see on CFTR, tobacco induced elevations in intracellular Ca 2+ may exert additional effects on the epithelia, as described above and could contribute to the inflammation/mucus secretion seen with tobacco exposure by triggering cytokine release and mucin secretion.…”

Endo-lysosomal TRP mucolipin-1 channels trigger global ER Ca2+ release and Ca2+ influx

“…They are likely filled by Ca 2+ -H + exchange (Melchionda et al, 2016) and express members of the transient receptor potential mucolipin (TRPML) and two-pore channel (TPC) families to effect Ca 2+ release (Grimm et al, 2012; Kiselyov et al, 2012; Patel, 2015; Waller-Evans and Lloyd-Evans, 2015). Three TRPML isoforms are present in humans (García-Añoveros and Wiwatpanit, 2014).…”