The Shank And Homer Families

The Shank and Homer protein families are two major components of the PSD that directly interact with each other.

Shank, also known as proline-rich synapse-associated protein (ProSAP), somatostatin receptor interacting protein (SSTRIP), cortactin-binding protein (cortBP), Synamon and Spank, is a large scaffold protein whose multidomain organization consists of an ankyrin repeat near the N-terminal, followed by an SH3, a PDZ domain, a long proline-rich region, and a sterile alpha motif domain (SAM) at the C-terminus66. Shank proteins (codified by three genes, Shank1-3) molecularly link two glutamate receptor subtypes: NMD A receptors and type-I mGluRs. The Shank PDZ domain binds to the C-terminal of GKAP. The Homer interaction with the proline-rich domain ensures the association of Shank with type I mGluRs.

Homer proteins are encoded by three genes (Homer 1-3), and typically consist of an N-terminal EVH1 domain followed by a coiled-coil domain that mediates dimerization with other Homer proteins. The Ena/VASP homology 1 (EVH1) domain of Homer1 binds to a PPXXF or a very similar sequence motif present in Shank, mGluR1/5, inositol-1,4,5-trisphosphate (IP3) receptor, ryanodine receptor, and to different members of the TRPC family of ion channels67,68. Through their ability to self-associate, Homer isoforms containing the coiled-coil domain (termed "CC-Homer" or Homer1b for the Homer1 gene) can physically and functionally link the proteins and receptors that bind to the EVH1 domain. Homer1a is a short-splice variant of Homer1 that contains the EVH1 domain but lacks the coiled-coil domain. Importantly, Homer1a expression is induced at mRNA level by synaptic activity.

There is consistent experimental evidence suggesting that Homer1a functions as a natural dominant negative protein, because it cannot dimerize. For example, Homer1a overexpression attenuates mGluR-evoked intracellular calcium release, probably by interfering with Homer-mediated coupling between type I mGluRs and IP3 receptors; similarly, Homer1a inhibits the Homer1b control of mGluR1/5 constitutive activity69 and disassembles the TRPC1-Homer-IP3R complex by inducing TRPC1 channel activation68.

The overexpression of Shank1 and Homer1b in hippocampal neurons accelerates the maturation of filopodial-like protrusions in mature spines, and promotes the enlargement of mature spines (which acquire the classical mushroom shape) without increasing their number. Shank and Homer also cooperate to promote the accumulation of PSD proteins in dendritic spines such as GKAP and NR1, and increase the F-actin content of spines70.

Roussignol et al. (2005) have more recently shown that the overexpression of Shank3 in cerebellum granule cells induces dendritic spine and synapse formation by recruiting different subtypes of glutamate receptors, whereas the inhibition of Shank3 expression in hippocampal neurons reduces the number of dendritic spines. One feature of the global effect of Shank on synapse maturation is that its overexpression also induces the maturation of the presynaptic compartment70,71.

It is therefore not surprising that, like PSD-95, Shank and Homer interact with a number of actin-binding proteins. Shank binds to cortactin, Abp172, fodrin73, the Rac1 and Cdc42 exchange factor PPIX74, and Cdc42-binding protein IRSp5375; and Homer binds to Rho GTPase-activating protein oligophrenin-176. Interestingly, the interaction of Shank1 with Homer seems to be essential for inducing spine maturation, and the interaction with cortactin seems to be equally important for Shank371.

Shank1 and Homer1b can also recruit the entire ER compartment to dendritic spines, which may contribute to their enlargement effect77. The ability of Shank1 and Homer1 to promote spine morphogenesis depends on their ability to form a complex with each other, and correlates with their accumulation in spines70,78. Interestingly, Homer 1a disrupts the interaction between full-length Homer1b and Shank, and inhibits the synaptic targeting of both proteins78. As a consequence, the overexpression of Homer1a destabilizes synapses and decreases the number and size of dendritic spines, also reducing the synapse number of both AMPA and NMDA receptors. In this case, the actions of Homer1a may contribute to the global activity-dependent loss of spines in a neuron, and the negative regulation of unstimulated synapses78 (Figure 18.3).

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