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
Source: PubMed


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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    • "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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    Neurobiology of aging 11/2013; 35(4). DOI:10.1016/j.neurobiolaging.2013.09.032 · 5.01 Impact Factor
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    • "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 [12], [13], S-SCAM [14], CIPP [15]. 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 [13], [16]–[18]. "
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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.
    PLoS ONE 06/2012; 7(6):e39585. DOI:10.1371/journal.pone.0039585 · 3.23 Impact Factor
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    • "Interestingly, Kir channels have functional PDZ binding domains (Yoo et al., 2004) and analysis of Kir4.1 and Kir3.3 sequences with the Eukaryotic Linear Motif (ELM) resource for functional sites in proteins ( reveals consensus PDZ1 motifs in the extreme C-terminal region of both proteins. Whereas functional analysis of PDZ domains on Kir proteins suggests that Kir3.3 does not bind PDZ sequences (Nehring et al., 2000), a number of studies have shown that Kir4.1 does (Horio et al., 1997; Kurschner et al., 1998; Tanemoto et al., 2004; Tanemoto et al., 2005). Thus, given that previous results from analysis of locus–locus interactions detected epistasis between the distal chromosome 1 kainate seizure susceptibility QTL and the kainate susceptibility QTL on mid-chromosome 4 (Ferraro et al., 1997), it is possible that a potential functional relationship exists between Mpdz and the product of the chromosome 1 QTL. "
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