{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nADAM22, a member of the ADAM gene family uniquely expressed in the nervous system, is implicated in mediating cell–cell and cell–matrix interactions, likely through integrin binding. Its high and restricted expression in neural tissues suggests roles in neuronal adhesion and the establishment of specialized membrane domains."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, ADAM22 functions as a pivotal component of axonal protein complexes. It interacts with Kv1 potassium channels and recruits membrane-associated guanylate kinases (MAGUKs) such as PSD-93 and PSD-95, thereby facilitating the organization and clustering of Kv1 channels at juxtaparanodes and other axonal regions. In this role, ADAM22 contributes to maintaining proper neuronal excitability without affecting the intrinsic channel properties."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nADAM22 also serves as a receptor for secreted leucine-rich glioma-inactivated proteins (LGI1 and LGI4), forming an essential synaptic organizing complex. Through these interactions, ADAM22 modulates synaptic strength and contributes to the maturation of excitatory synapses by coordinating the incorporation and stabilization of postsynaptic scaffolding proteins like PSD-95. This LGI1–ADAM22 signaling axis is critical not only for synaptic development but also for maintaining the precise nanoscale architecture required for effective neurotransmission, with disruptions linked to epileptic encephalopathy."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in channel clustering and synaptic organization, ADAM22 is embedded in wider protein networks. It is a component of the Caspr2 interactome, linking it to a complex assemblage of adhesion molecules and channels implicated in neurodevelopmental disorders such as autism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the central nervous system, ADAM22 exhibits emerging functions in non-neuronal contexts. It has been implicated in cardiac hypertrophy, suggesting a role in the remodeling processes that may lead to heart failure. Furthermore, ADAM22 is targeted by miR-221-3p in macrophages, modulating foam cell formation and apoptosis during atherosclerosis, and its involvement is being explored in the context of pituitary adenoma invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Koji Sagane, Kazuhiro Hayakawa, Junko Kai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Neurosci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2202-6-33"}], "href": "https://doi.org/10.1186/1471-2202-6-33"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15876356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15876356"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yasuhiro Ogawa, Juan Oses-Prieto, Moon Young Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ADAM22, a Kv1 channel-interacting protein, recruits membrane-associated guanylate kinases to juxtaparanodes of myelinated axons."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.4661-09.2010"}], "href": "https://doi.org/10.1523/JNEUROSCI.4661-09.2010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20089912"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20089912"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Koji Sagane, Yasushi Ishihama, Hachiro Sugimoto "}, {"type": "b", "children": [{"type": "t", "text": "LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biol Sci (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/ijbs.4.387"}], "href": "https://doi.org/10.7150/ijbs.4.387"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18974846"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18974846"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Kathryn L Lovero, Yuko Fukata, Adam J Granger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1511910112"}], "href": "https://doi.org/10.1073/pnas.1511910112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26178195"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26178195"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Yuko Fukata, Xiumin Chen, Satomi Chiken, et al. "}, {"type": "b", "children": [{"type": "t", "text": "LGI1-ADAM22-MAGUK configures transsynaptic nanoalignment for synaptic transmission and epilepsy prevention."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.2022580118"}], "href": "https://doi.org/10.1073/pnas.2022580118"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33397806"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33397806"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Ning Chen, Frank Koopmans, Aaron Gordon, et al. 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