The insulin receptor substrate of 53 kDa (IRSp53) is a target of the small GTPase cdc42 which is strongly enriched in the postsynaptic density of excitatory synapses. IRSp53 interacts with the postsynaptic shank1 scaffolding molecule in a cdc42 regulated manner. The functional significance of the cdc42/ IRSp53 pathway in postsynaptic sites is however, unclear. The generation of excitatory synapses in the central nervous system requires a complex assembly process in which elements of the postsynaptic receptor apparatus are assembled at postsynaptic sites on dendrites. In many cases, glutamatergic synapses are localized on the heads of dendritic spines (Harris and Kater 1994; see review by Hering and Sheng 2001). During maturation postsynaptic proteins accumulate at the synapse, as exemplified in several studies by the appearance of clusters of the postsynaptic marker PSD-95 (Friedman et al. 2000;Okabe et al. 2001). Via its PDZ domains, PSD-95 is one of the major anchoring proteins for postsynaptic transmitter receptors and ion channels (Kim et al. 1995;Kornau et al. 1995). Through an intricate network of protein interactions, a large protein complex of up to 100 proteins is assembled at the spine heads around the PSD-95/transmitter receptor complex (Husi et al. 2000;Walikonis et al. 2000;Li et al. 2004) which has been termed the postsynaptic density (PSD). The function of the PSD appears to be to physically link postsynaptic receptors to signalling molecules, and to provide stable attachment of the receptors to the actin-based cytoskeleton of the dendritic spine. Shank proteins (shank1-3, also known as SSTRIP, ProSAP, synamon or CortBP) constitute another group of postsynaptic scaffolding molecules which link transmitter receptors (Kreienkamp et al. 2000;Naisbitt et al. 1999;Yao et al. 1999;Zitzer et al. 1999) to actin binding proteins (Du et al. 1998;Boeckers et al. 2001;Okamoto et al. 2001). Overexpression of shank1 in neurones leads to enhanced maturation of dendritic spines . We and others have recently identified IRSp53 as an interaction partner for shank1 (Bockman et al. 2002;Soltau et al. 2002). A proline-rich region of shank1 binds to the SH3 domain of IRSp53 in a cdc42-regulated manner (Soltau et al. 2002). These data suggested that shank1 might be an effector molecule of cdc42 in an undefined regulatory pathway. Here, we show that IRSp53, via binding to a PDZ domain of the PSD-95 molecule, mediates the formation of a triple complex consisting of shank1 and PSD-95. Our data suggest that one result of cdc42/IRSp53 signalling is the regulated assembly of a macromolecular complex between shank and PSD-95 proteins.Received January 14, 2004; revised manuscript received March 19, 2004; accepted March 23, 2004. Address correspondence and reprint requests to Hans-Jürgen Kreienkamp, Institut für Zellbiochemie und klinische Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: kreienkamp@uke.uni-hamburg.deAbbreviations used: IRSp53, insulin receptor su...
The calcium-independent receptors for latrotoxin (CIRL1-CIRL3) constitute a family of seven-transmembrane receptors with an unsually large N-terminal extracellular domain which comprises several motifs usually found in cell adhesion molecules. By yeast two-hybrid screening, we have identified the intracellular C-termini of CIRL1 and CIRL2 as interaction partners of the PDZ domain of the proline-rich synapse-associated protein (ProSAP)/somatostatin receptor-interacting protein (SSTRIP) family of postsynaptic proteins (SSTRIP, ProSAP1 and ProSAP2, also known as shank1-shank3 respectively). Overlay assays indicate that the ProSAP1/shank2 PDZ domain in particular interacts strongly with the C-terminus of CIRL1 and CIRL2. Co-immunoprecipitation of ProSAP1 and CIRL1 (but not CIRL2) from rat brain extracts indicates that this interaction also occurs in vivo in rat brain. The known postsynaptic localization of ProSAP1, as well as our observation that CIRL1 (but not CIRL2) is enriched in postsynaptic density preparations from the rat brain, suggests that CIRL1 is localized pre- as well as post-synaptically in the central nervous system.
The calcitonin (CT) receptor (CTR) was cloned by Goldring in 1991. For all the other receptors of the CT family of hormones and neuropeptidcs receptor-activity-modifying proteins (RAMP) arc required for ligand recognition. Thus a new principle for the functional expression of G protein-coupled receptors has been discovered by Foord in 1998. The initially orphan CT receptor-like receptor (CRLR) was identified as a calcitonin gene-related peptidc (CGRP) receptor when co-expressed with RAMPI. The same receptor is specific for adrenomedullin (AM) in the presence of RAMP2. I n the absence of RAMP the C T R with 60% homology to the CRLR predominantly recognizes CT. An amylin/CGRP receptor is revealed when the C T R is co-expressed with RAMPI. Together with RAMP3 the C T R interacts with amylin alone. Two C G R P receptor isotypes, the CRLRIRAMPI antagonized by CGRP(8-37) and not by salmon CT(8-32), and the CTR/RAMPl amagonized by salmon CT(8-32) can be differentiated. Thus noncovalent association of two class I1 G protein-coupled receptors with three RAMP results in heterodimeric RAMP/receptor complexes essential for the recognition of CGRP, AM or amylin at the cell surface.c11 Receptor component protein (rcp): a member of a multiprotein complex required for G protein-coupled signal transductionThe calcitonin gene-related peptide (CGRP)-receptor component protein (RCP) is a 17 kDa intracellular peripheral membrane protein required for signal transduction at the G protein-couplcd receptor calcitonin receptor-like receptor (CRLR). CRLR functions as a C G R P receptor when co-expressed with an accessory protein named receptor activity modifying protein-1 (RAMPI), and as an adrenomedullin receptor when co-expressed with RAMP2. When RCP was depleted from NIH3T3 cells using antisense strategy, loss of R C P protein correlated with dccrcased CAMP production by C G R P or adrenomedullin in the antisense cells. In contrast, loss of R C P had n o effect o n ligand binding. Therefore, R C P is not acting as a chaperone for CRLR; instead RCP couples CRLR to the cellular signal transduction machinery. RCP co-immunoprecipitates with CRLR, RAMPI, and RAMP2 from NIH3T3 cells. This suggests that a functional C G R P or adrenomedullin receptor is a trimer of proteins: a ligand binding protein (CRLR), an accessory protein that determines pharmacologic specificity (RAMPI or RAMPZ), and a protein that couples the receptor to the cellular signal transduction pathway (RCP).The calcium independent receptors for latrotoxin (CIRLI -3) constitute a family of seven transmembrane receptors with an unsually large N-terminal, extracellular domain which comprises several motifs usually found in cell adhesion molecules. By yeast two hybrid screening, we have identified the intracellular Cterminus of CIRLl and CIRL2 as interaction partners of the PDZ domain of the ProSAP/SSTRIP family of postsynaptic proteins (SSTRIP, ProSAPl and 2, also known as shankl-3). Overlay assays indicate that especially the ProSAPl PDZ domain interacts strongly with the C-...
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