Recent progress in understanding the intracellular domain's gating and functional roles in trimeric ligand-gated ion channels

Ligand-gated ion channels are a large category of essential ion channels, whose superfamily members may modulate their state by binding to specific ligands, allowing specific ions to pass through the cell membrane. Purinergic ligand- gated ion channel(P2X)and ASIC (acid-sensitive ion channel) are representative members of trimeric ligand-gated ion channels. Recent studies have shown that structural differences in the intracellular domain of P2X receptors (P2XR) may determine the desensitization process. The lateral fenestrations of P2XR potentially serve as a pathway for ion conduction and play a decisive role in ion selectivity. Phosphorylation of numerous amino acid residues in the P2XR is involved in regulating the activity of ion channels. Additionally, the P2XR interacts with other ligand-gated ion channel such as NMDA receptor, GABA receptor, 5-HT₃ receptor and nACh receptor, mediating physiological processes such as synaptic plasticity. Conformational changes in the intracellular domain of the ASICs expose binding sites for intracellular signal partners, facilitating metabolic signal transduction. Amino acids such as Val16, Ser17, Ile18, Gln19 and Ala20 in the ASICs participate in channel opening and membrane expression. ASICs can also bind to intracellular proteins, such as CIPP and p11, to regulate channel function. Many phosphorylation sites at the C-terminus and N-terminus of ASICs are involved in the regulation of receptors. Furthermore, ASICs are involved in various physiological and pathophysiological processes, including pain, ischemic stroke, psychiatric disorders, and neurodegenerative disease. In this article, we review the roles of the intracellular domains of these trimeric ligand-gated ion channels in channel gating as well as their physiological and pathological functions, in order to provide new insights for drug discovery targeting them.