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.

Korean J Physiol Pharmacol 2023;27:311-323 https://doi.org/10.4196/kjpp.2023.27.4.311

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