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The Journal of Neuroscience, August 1, 2002, 22(15):6415-6425

Postsynaptic Targeting of Alternative Postsynaptic Density-95 Isoforms by Distinct Mechanisms

Dane M. Chetkovich^{1, 2, *}, Robert C. Bunn^{1, *}, Sheng-Han Kuo¹, Yoshimi Kawasaki¹, Minoree Kohwi¹, and David S. Bredt¹

Departments of ¹ Physiology and ² Neurology, University of California, San Francisco, San Francisco, California 94143

Members of the postsynaptic density-95 (PSD95)/synapse-associated protein-90 (SAP90) family of scaffolding proteins contain a common set of modular protein interaction motifs including PDZ (postsynaptic density-95/Discs large/zona occludens-1), Src homology 3, and guanylate kinase domains, which regulate signaling and plasticity at excitatory synapses. We report that N-terminal alternative splicing of PSD95 generates an isoform, PSD95 that contains an additional "L27" motif, which is also present in SAP97. Using yeast two hybrid and coimmunoprecipitation assays, we demonstrate that this N-terminal L27 domain of PSD-95, binds to an L27 domain in the membrane-associated guanylate kinase calcium/calmodulin-dependent serine kinase, and to Hrs, an endosomal ATPase that regulates vesicular trafficking. By transfecting heterologous cells and hippocampal neurons, we find that interactions with the L27 domain regulate synaptic clustering of PSD95. Disrupting Hrs-regulated early endosomal sorting in hippocampal neurons selectively blocks synaptic clustering of PSD95 but does not interfere with trafficking of the palmitoylated isoform, PSD95. These studies identify molecular and functional heterogeneity in synaptic PSD95 complexes and reveal critical roles for L27 domain interactions and Hrs regulated vesicular trafficking in postsynaptic protein clustering.

Key words: neuron; synapse; protein sorting; endosome; PSD95; Hrs

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^* D.M.C. and R.C.B. contributed equally to this work

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22156415-11$05.00/0

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