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The Journal of Neuroscience, May 4, 2005, 25(18):4587-4592; doi:10.1523/JNEUROSCI.4822-04.2005

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Key Role of the Postsynaptic Density Scaffold Proteins Shank and Homer in the Functional Architecture of Ca²⁺ Homeostasis at Dendritic Spines in Hippocampal Neurons

Carlo Sala,¹ Gautier Roussignol,² Jacopo Meldolesi,³ and Laurent Fagni²

¹Cellular and Molecular Pharmacology Section, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, and Department of Pharmacology, University of Milan, 20129 Milan, Italy, ²Institut de Génomique Fonctionelle, Unité Mixte de Recherche 5203, 34094 Montpellier, France, and ³Department of Neuroscience, Vita-Salute San Raffaele University, and Center of Excellence in the Physiopathology of Cell Differentiation, 20132 Milan, Italy

A key aspect of postsynaptic function, also important for plasticity, is the segregation within dendritic spines of Ca²⁺ rises attributable to release from intracellular stores. Previous studies have shown that overexpression in hippocampal neurons of two postsynaptic density (PSD) scaffold proteins, Shank1B and Homer1b, induces spine maturation, including translocation of the intracellular Ca²⁺ channel inositol trisphosphate receptor (IP₃R). The structural and functional significance of these processes remained undefined. Here, we show that in its relocation, IP₃R is accompanied by other endoplasmic reticulum (ER) proteins: the Ca²⁺ pump sarcoendoplasmic reticulum calcium ATPase, the lumenal Ca²⁺-binding protein calreticulin, the ER lumen-addressed green fluorescent protein, and, to a lesser extent, the membrane chaperone calbindin. The specificity of these translocations was demonstrated by their inhibition by both a Shank1 fragment and the dominant-negative Homer1a. Activation in Shank1B-transfected neurons of the metabotropic glutamatergic receptors 1/5 (mGluRs1/5), which induce IP₃ generation with ensuing Ca²⁺ release from the stores, triggered considerable increases in Ca²⁺-dependent responses: activation of the big K⁺ channel, which was revealed by patch clamping, and extracellular signal-regulated protein kinase (ERK) phosphorylation. The interaction of Shank1B and Homer1b appears as the molecular mechanism linking mGluRs1/5, strategically located in the spines, to IP₃R with the integration of entire ER cisternas in the PSD and with consequences on both local Ca²⁺ homeostasis and overall neuronal signaling.

Key words: postsynaptic density; ERK1/2; mGluR; ER calcium stores; big K⁺ channel; Shank; Homer

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Received Nov 25, 2004; revised March 21, 2005; accepted March 28, 2005.

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