Neuropilin and tolloid-like protein 1 (NETO1)

Neuropilin and tolloid-like protein 1 (NETO1) is a brain-expressed transmembrane protein containing two extracellular CUB domains and one low-density lipoprotein receptor class A domain. It plays an essential role as an auxiliary subunit of neuronal NMDA receptor (NMDAR) complexes, especially maintaining the abundance of synaptic NR2A-containing NMDARs. NETO1 is primarily localized to the postsynaptic density of excitatory synapses in the brain, where it interacts with core NMDAR subunits and scaffolding proteins such as PSD-95 to regulate synaptic plasticity, cognition, and memory. Loss of NETO1 disrupts synaptic NMDAR composition, reduces long-term potentiation, and impairs learning and memory in animal models. An inherited deficit of synaptic functioning due to NETO1 loss can be pharmacologically rescued (at least in mice) by positive AMPA modulators such as CX546, suggesting both a mechanistic and therapeutic relevance for disease states involving synaptic plasticity deficits[1][2][3][4].

Other names

NETO1BTCL1BCTL1Neuropilin and tolloid like 1Neuropilin and tolloid-like protein 1Brain-specific transmembrane protein containing 2 CUB and 1 LDL-receptor class A domains protein 1Neuropilin (NRP) and tolloid (TLL)-like 1

Modulators such as CX546 act indirectly by enhancing synaptic NMDAR currents through positive allosteric modulation of AMPA receptors, counteracting synaptic deficits due to NETO1 loss[1]