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GLOSSARY
- AD=
- Alzheimer disease;
- ADAM=
- A disintegrin and metalloproteinase;
- ADEAF=
- autosomal dominant partial epilepsy with auditory features;
- ADTLE=
- autosomal dominant familial temporal lobe epilepsy;
- APP=
- amyloid precursor protein;
- EPTP=
- epitempin;
- Kv=
- voltage-gated potassium;
- LGI=
- leucine-rich, glioma inactivated;
- LRR=
- leucine-rich repeats;
- NgR1=
- Nogo receptor 1;
- PSD-95=
- postsynaptic density–95;
- SAP97=
- synapse-associated protein 97
A disintegrin and metalloproteinase (ADAM) proteins are multifunctional transmembrane proteins that are important for development, communication, and plasticity in the nervous system. Some ADAMs, such as ADAM10, have metalloproteinase activity and cut off or shed extracellular portions of transmembrane proteins, such as amyloid precursor protein (APP) and N-cadherins. Others, such as ADAM22 and ADAM23, are primarily involved in direct cell–cell signaling through their disintegrin domain. Leucine-rich, glioma inactivated (LGI)1 is a secreted neuronal protein that binds to both presynaptic ADAM23 and postsynaptic ADAM22; via these interactions, LGI1 forms part of macromolecular complexes with voltage-gated potassium (K+) channels and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Studies on ADAM knockout mice and mice expressing LGI1 mutations have provided insight into the normal function of these proteins. LGI1 may have an important role in transsynaptic interactions for normal development, activity, and plasticity of excitatory synapses in the CNS. The LGI-ADAM22 interactions may also participate in axonal growth and myelination. LGI1 mutations are linked to autosomal dominant familial temporal lobe epilepsy (ADTLE); anti-LGI1 antibodies are associated with limbic encephalitis. ADAM10 is the most important α-secretase involved in nonamyloidogenic processing of APP; it may therefore be a potential therapeutic target in Alzheimer disease (AD). The function of ADAM proteins and their ligands have been recently reviewed.1,2
ADAM PROTEINS
General structure and expression.
ADAM proteins are transmembrane proteins that have multiple functions.1,2 They consist of several domains, including an amino (N)-terminal propeptide domain, a metalloproteinase domain, a disintegrin domain, a transmembrane domain, a cysteine-rich region with an epidermal growth factor like sequence, and a cytoplasmic carboxy (C)-terminal tail involved in intracellular signaling1,2 (figure 1). Among the 33 known mammalian ADAMs, at least 17 are expressed in the nervous system; important examples are ADAM9, ADAM10, ADAM12, ADAM17, ADAM22, and ADAM23. Individual members show variable …
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