CIPP, a Novel Multivalent PDZ Domain Protein, Selectively Interacts with Kir4.0 Family Members, NMDA Receptor Subunits, Neurexins, and Neuroligins
Department of Developmental Neurobiology, Saint Jude Children's Research Hospital, Memphis, Tennessee, 38105, USA. Molecular and Cellular Neuroscience
(Impact Factor: 3.84).
07/1998; 11(3):161-72. DOI: 10.1006/mcne.1998.0679
We report a novel multivalent PDZ domain protein, CIPP (for channel-interacting PDZ domain protein), which is expressed exclusively in brain and kidney. Within the brain, the highest CIPP mRNA levels were found in neurons of the cerebellum, inferior colliculus, vestibular nucleus, facial nucleus, and thalamus. Furthermore, we identified the inward rectifier K+ (Kir) channel, Kir4.1 (also called "Kir1.2"), as a cellular CIPP ligand. Among several other Kir channels tested, only the closely related Kir4.2 (or "Kir1.3") also interacted with CIPP. In addition, specific PDZ domains within CIPP associated selectively with the C-termini of N-methyl-D-aspartate subtypes of glutamate receptors, as well as neurexins and neuroligins, cell surface molecules enriched in synaptic membranes. Thus, CIPP may serve as a scaffold that brings structurally diverse but functionally connected proteins into close proximity at the synapse. The functional consequences of CIPP expression on Kir4.1 channels were studied using whole-cell voltage clamp techniques in Kir4.1 transfected COS-7 cells. On average, Kir4.1 current densities were doubled by cotransfection with CIPP.
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- ") Promotes filopodia formation (Disanza et al., 2013) Neuronal polarity (Drees and Gertler, 2008; Neukirchen and Bradke, 2011) Wave-1 (Miki et al., 2000) Links Rac and Wave (Miki et al., 1998; Miki et al., 2000) Spines, synaptic plasticity, and memory (Hazai et al., 2013; Kim et al., 2006; Soderling et al., 2007) Wave-2 (Miki et al., 2000) Links Rac and Wave (Miki et al., 1998; Miki et al., 2000) Likely dendritic spines (Choi et al., 2005; Ito et al., 2010; Lee et al., 2006; Soderling and Scott, 2006) PDZ-B CIPP (Alpi et al., 2009; Barilari and Dente, 2010) Form the CIPP-Cypin-IRSp53 complex (Barilari and Dente, 2010) Synaptic membrane protein clustering (Kurschner et al., 1998) ASD and Schizophrenia (Kenny et al., 2014) MALS/LIN-7 (Hori et al., 2003) May translocate IRSp53 to cell ecell contacts (Hori et al., 2003) Synapse development and function (Mizuno et al., 2015) ASD (Mizuno et al., 2015) PSD-93 (Choi et al., 2005) Synaptic localization of IRSp53 (Choi et al., 2005) Postsynaptic protein scaffolding (Sheng and Kim, 2011) ASD (Egger et al., 2014) PSD-95 (Choi et al., 2005; Soltau et al., 2004) Synaptic localization of IRSp53 (Choi et al., 2005) Postsynaptic protein scaffolding (Sheng and Kim, 2011) ASD and William's syndrome (Feyder et al., 2010) Schizophrenia (Balan et al., 2013; Purcell et al., 2014) Table 2 Electrophysiological and behavioral phenotypes of IRSp53 À/À mice. "
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ABSTRACT: IRSp53 (also known as BAIAP2) is a multi-domain scaffolding and adaptor protein that has been implicated in the regulation of membrane and actin dynamics at subcellular structures, including filopodia and lamellipodia. Accumulating evidence indicates that IRSp53 is an abundant component of the postsynaptic density at excitatory synapses and an important regulator of actin-rich dendritic spines. In addition, IRSp53 has been implicated in diverse psychiatric disorders, including autism spectrum disorders, schizophrenia, and attention deficit/hyperactivity disorder. Mice lacking IRSp53 display enhanced NMDA (N-methyl-D-aspartate) receptor function accompanied by social and cognitive deficits, which are reversed by pharmacological suppression of NMDA receptor function. These results suggest the hypothesis that defective actin/membrane modulation in IRSp53-deficient dendritic spines may lead to social and cognitive deficits through NMDA receptor dysfunction.
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Available from: Peter Ronald Dodd
- "All neuroligin isoforms are post-synaptic transmembrane proteins. NLGN1 is usually expressed in neurons at excitatory postsynaptic sites and found connected to NMDAR, postsynaptic densitye95 (PSD-95) and Synaptic scaffolding molecule (S-SCAM) at the synaptic junction and postsynaptic densities (Hirao et al., 1998; Ichtchenko et al., 1996; Kurschner et al., 1998; Song et al., 1999). NLGN2 is expressed mainly at inhibitory neuronal sites in CNS but is also expressed in pancreas, lung endothelia, and colon (Varoqueaux et al., 2004). "
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ABSTRACT: Synaptic damage is a critical hallmark of Alzheimer's disease, and the best correlate with cognitive impairment ante mortem. Synapses, the loci of communication between neurons, are characterized by signature protein combinations arrayed at tightly apposed pre- and post-synaptic sites. The most widely studied trans-synaptic junctional complexes, which direct synaptogenesis and foster the maintenance and stability of the mature terminal, are conjunctions of presynaptic neurexins and postsynaptic neuroligins. Fluctuations in the levels of neuroligins and neurexins can sway the balance between excitatory and inhibitory neurotransmission in the brain, and could lead to damage of synapses and dendrites. This review summarizes current understanding of the roles of neurexins and neuroligins proteolytic processing in synaptic plasticity in the human brain, and outlines their possible roles in β-amyloid metabolism and function, which are central pathogenic events in Alzheimer's disease progression.
Available from: Ronald S Petralia
- "NMDA receptor NR2 subunit cytoplasmic tails contain a PDZ-binding domain at the extreme C-terminus that can associate with all four members of the PSD-95 family of membrane-associated guanylate kinases (MAGUKs; PSD-93, PSD-95, SAP97, and SAP102), as well as with other MAGUKs and PDZ domain-containing proteins such as MALS , , S-SCAM , CIPP . Imaging of NR2B transport vesicles in dendrites have revealed that NR2B-containing vesicles travel along microtubules and this transport appears to be at least in part mediated by the interaction with a multi-molecular protein transport complex comprised of the kinesin motor KIF-17, mLin-10, mLin-7, mLin-2/CASK and SAP97 , –. "
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ABSTRACT: NMDA receptor NR2A/B subunits have PDZ-binding domains on their extreme C-termini that are known to interact with the PSD-95 family and other PDZ proteins. We explore the interactions between PSD-95 family proteins and the NR2A/B cytoplasmic tails, and the consequences of these interactions, from the endoplasmic reticulum (ER) through delivery to the synapse in primary rat hippocampal and cortical cultured neurons. We find that the NR2A/B cytoplasmic tails cluster very early in the secretory pathway and interact serially with SAP102 beginning at the intermediate compartment, and then PSD-95. We further establish that colocalization of the distal C-terminus of NR2B and PSD-95 begins at the trans-Golgi Network (TGN). Formation of NR2B/PSD-95/SAP102 complexes is dependent on the PDZ binding domain of NR2B subunits, but association with SAP102 and PSD-95 plays no distinguishable role in cluster pre-formation or initial targeting to the vicinity of the synapse. Instead the PDZ binding domain plays a role in restricting cell-surface clusters to postsynaptic targets.
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