Narp and NP1 Form Heterocomplexes that Function in Developmental and Activity-Dependent Synaptic Plasticity

Abstract

Narp is a neuronal immediate early gene that plays a role in excitatory synaptogenesis. Here, we report that native Narp in brain is part of a pentraxin complex that includes NP1. These proteins are covalently linked by disulfide bonds into highly organized complexes, and their relative ratio in the complex is dynamically dependent upon the neuron's activity history and developmental stage. Complex formation is dependent on their distinct N-terminal coiled-coil domains, while their closely homologous C-terminal pentraxin domains mediate association with AMPA-type glutamate receptors. Narp is substantially more effective in assays of cell surface cluster formation, coclustering of AMPA receptors, and excitatory synaptogenesis, yet their combined expression results in supraadditive effects. These studies support a model in which Narp can regulate the latent synaptogenic activity of NP1 by forming mixed pentraxin assemblies. This mechanism appears to contribute to both activity-independent and activity-dependent excitatory synaptogenesis.

Structural Characterization of PTX3 Disulfide Bond Network and Its Multimeric Status in Cumulus Matrix Organization

“…Moreover Cys 179 and Cys 357 are conserved among the long neuronal pentraxins Narp and NP1 (33,34). Some recent evidence showed that corresponding residues in these proteins do not participate in the formation of multimers (35), strongly suggesting that the disulfide bond Cys 179 -Cys 357 described here is formed within rather than between PTX3 subunits.…”

“…Neuronal pentraxin 2 (NP2), also known as neuronal activity-regulated pentraxin (Narp), and neuronal pentraxin 1 (NP1), two members of the long pentraxin subfamily selectively expressed in brain, are covalently linked by disulfide bonds into highly organized complexes (33,34). The number of protein molecules in these complexes is dynamically dependent upon the activity history of the neurons and the brain developmental stage (35). However, little is known about the effect of protein oligomerization on PTX3 biological activity.…”

Neuronal Pentraxins Mediate Synaptic Refinement in the Developing Visual System

“…Although NP1 and NP2 are secreted when expressed alone, they can be tethered to the cell membrane when expressed as heteromultimers with NPR. NP2 (also called Narp) is dramatically upregulated by neuronal activity (Tsui et al, 1996) and can induce clustering of AMPA receptors when coexpressed in heterologous cells (O'Brien et al, 1999;Xu et al, 2003). On the basis of these properties and their homology to short pentraxins in the innate immune system that mark cells for phagocytosis and degradation by opsonization, we tested the hypothesis that NPs are required for synapse refinement and elimination in the developing CNS (Dodds et al, 1995(Dodds et al, , 1997.…”

Regulation of AMPA receptors and synaptic plasticity

“…This family consists of neuronal-activity-regulated pentraxin (Narp) and neuronal pentraxin 1 (NP1), both secreted proteins homologous to the serum pentraxins (Schlimgen et al, 1995;Tsui et al, 1996), and neuronal pentraxin receptor (NPR), an integral membrane protein (Dodds et al, 1997). Narp and NP1 coimmunoprecipitate with AMPARs in heterologous cells (Xu et al, 2003), and Narp-expressing HEK cells seeded on neurons recruit GluR1 to sites where they contact neuronal dendrites . Recently, Sia et al (2007) described that the presynaptically secreted NP1 and NPR bind to the GluR4 N-terminal domain and are critical trans-synaptic factors for GluR4 recruitment to synapses.…”