Korean J Physiol Pharmacol.  2023 Jul;27(4):311-323. 10.4196/kjpp.2023.27.4.311.

Unveiling the impact of lysosomal ion channels: balancing ion signaling and disease pathogenesis

• Jung Y
• Kim W
• Shin NK
• Bae YM
• Wie J

• KMID: 2544133
• DOI: http://doi.org/10.4196/kjpp.2023.27.4.311

Abstract

Ion homeostasis, which is regulated by ion channels, is crucial for intracellular signaling. These channels are involved in diverse signaling pathways, including cell proliferation, migration, and intracellular calcium dynamics. Consequently, ion channel dysfunction can lead to various diseases. In addition, these channels are present in the plasma membrane and intracellular organelles. However, our understanding of the function of intracellular organellar ion channels is limited. Recent advancements in electrophysiological techniques have enabled us to record ion channels within intracellular organelles and thus learn more about their functions. Autophagy is a vital process of intracellular protein degradation that facilitates the breakdown of aged, unnecessary, and harmful proteins into their amino acid residues. Lysosomes, which were previously considered protein-degrading garbage boxes, are now recognized as crucial intracellular sensors that play significant roles in normal signaling and disease pathogenesis. Lysosomes participate in various processes, including digestion, recycling, exocytosis, calcium signaling, nutrient sensing, and wound repair, highlighting the importance of ion channels in these signaling pathways. This review focuses on different lysosomal ion channels, including those associated with diseases, and provides insights into their cellular functions. By summarizing the existing knowledge and literature, this review emphasizes the need for further research in this field. Ultimately, this study aims to provide novel perspectives on the regulation of lysosomal ion channels and the significance of ion-associated signaling in intracellular functions to develop innovative therapeutic targets for rare and lysosomal storage diseases.

Figure

• 

  Fig. 1 Schematic lysosomal ion channels and transporters. The ion movements belong to ion channel directions. Lysosomal ion channels characterized permeability; TRPMLs (few divalent cations, and nonselective cations: yellow), TMEM175, BK (potassium ion: blue), ClC-7 (chloride and hydrogen: green), V-ATPase (hydrogen: black), and TPCs (sodium, and calcium: purple). Compared to the cytosol, lysosomal lumen has high concentrations of Na+, Ca2+, and H+ but not K+. BK, calcium-activated large-conductance K+ channel; TPC, two-pore channel.

• 

  Fig. 2 Interaction between ion channels and regulators. Amino acids and growth factors bind to receptors on the plasma membrane. PI3kinases increase the concentration of PIP3 from PtdIns(4,5)P2 (PIP2), which binds to the PH domain of AKT. This binding induces a con-formational change that affects downstream signaling pathways such as PIKfyve or mTORC1. AKT phosphorylation occurs at an important residue in the kinase domain (S308) by PDK1 and another residue (S473) in the C-terminal regulatory domain. Phosphorylation of AKT induces changes in PIKfyve, which converts PI(3)P2 to PI(3,5)P2 [25]. BK and TRPML1 channels are promoted by PI(3,5)P2 and reactive oxidative stress (ROS). AKT phosphorylation also inhibits TSC1/2, abolishing Rheb-induced phosphorylation of mTORC1 at residues S2481 and S2448 [26,27]. AMPK signaling is affected by glucose (activation) and setrin (inhibition), AMPK inhibits the mTORC1 [28,29]. TPCs are inhibited by mTORC1 when its domain that interacts with TPC is closed. V-ATPase regulated by mTOR1 through a regulator complex when binding with Rheb. TMEM175 activation requires aa conformational change in PH domain of AKT but does not associate AKT downstream pathways. mTORC1, mechanistic targets of rapamycin complex 1; AMPK, AMP-activated kinase; TPC, two-pore channel; BK, calcium-activated large-conductance K+ channel; TRPML, transient receptor potential mucolipin.

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