Actinbinding Proteins

It has been demonstrated that a number of actin-binding proteins (usually effectors of Rho and Rac GTPases regulated by Ca2+) control the actin cytoskeleton in dendritic spines. Most of them are formed by the concatenation of different protein interaction domains, and thus function as scaffolds assembled in multimolecular complexes.

We here describe the most important actin-binding scaffold proteins regulating dendritic spine morphology (Figure 18.2; Colorplate 11).

One of these is drebrin, an F-actin-binding protein, which is mainly expressed in neurons and highly concentrated in dendritic spines. Drebrin overexpression in cortical neurons increases the length of dendritic spines85, and its activity may be mediated by its binding to F-actin and other acting-regulatory proteins, such as profilin, myosin, and gelsolin. Also, it has more recently been shown86 that, in hippocampal neurons, drebrin promotes actin assembly and the synaptic clustering of PSD-95 in the PSD. Importantly, drebrin is redistributed to dendritic spines, together with an increase in F-actin content, after the induction of LTP in the dentate gyrus87, which suggests it is important in inducing F-actin polymerization and/or stabilization.

Like drebrin, profilin II and aa-catenin are recruited to spines by general synaptic activation and by NMDA receptors activation or LTP induction, and can induce actin polymerization and stabilization. Profilin is a small actin-binding protein that promotes actin polymerization by positioning the actin monomers at the barbed end of the growing F-actin. The accumulation of profilin II in dendritic spines persists for hours beyond the initiating stimulus and this depends on an increase in postsynaptic Ca2+ levels and, probably, on the association of profilin II with Ena/VASP family proteins. Profilin II stabilizes spine morphology in a mature state and suppresses dendritic spine motility by reducing actin dynamics88. These results suggest that profilin II plays a role in linking the activation of glutamate receptors with the actin-based stabilization of synapse morphology.

aA-catenin is a cadherin-associated protein and, together with P-catenin, links the adhesion molecules to the cytoskeleton and actin. Abe et al. (2004) have recently showed that, in the absence of aa-catenin, dendritic spines are more motile and their filopodia rapidly protrude and retract from the spine heads, a sign of unstable synaptic contacts. Conversely, the overexpression of aa-catenin accelerates dendritic spine maturation and decreases spine motility, thus suggesting that it promotes spine morphogenesis and stabilization. As it appears to accumulate in activated synapses, aN-catenin may mediate neural activity-dependent signals that stabilize synapses by suppressing motility and turnover89. One possible bidirectional interaction between the profilin/actin and cadherin/aN-catenin systems has been proposed in which neural activity contribute to changes in spine shape by modifying any of these molecular interactions89.

Spinophilin (or neurabin II) and neurabin I are two related F-actin-binding proteins with similar domain structures containing a PDZ and a coiled-coil domain that form homo- and heterodimers. Via its actin-binding domain, spinophilin (as its name suggests) is predominantly localized on the dendritic spines of pyramidal neurons; it seems to be required for the correct maturation of dendritic spines because knockout mice have more filopodia and immature spines and altered glutamatergic transmission90. Its activity may be related to its ability to bind PP1 phosphatase, thus regulating the phosphorylation state of PP1 substrates such as AMPA and NMDA glutamate receptors and the myosin regulatory light chain. In one case, spinophilin can modulate the stability of the actin cytoskeleton in spines by modulating the ion currents of glutamate receptors91; it may also regulate dendritic spine morphology by promoting the dephosphorylation of the myosin light chain, thus inhibiting the assembly and contractility of actin filaments92. On the contrary, neurabin I overexpression induces the formation of dendritic filopodia in immature cultured hippocampal neurons and promotes the enlargement of dendritic spines in older neurons93. Moreover, it has been recently shown that the neurabin I amino-terminal fragment, which contains the actin-binding domain, increases the density and length of dendritic spines also by increasing actin polymerization and spine motility94. This suggests that the neurabin I carboxy-terminal portion plays a negative regulatory role. It is not clear how spinophilin and neurabin I have opposite effect on spines, although they both bind a similar set of proteins in synapses. Finally, the coiled-coil domains of neurabin I and spinophilin have more recently been found to interact with Lfc, a Rho GEF that regulates the Rho-dependent organization of F-actin in spines95.

a-actinin-2, one of the a-actinin isoforms, is a member of the spectrin/dystrophin family of actin-binding proteins, and is enriched in dendritic spines of pyramidal neurons. Its overexpression increases the length and density of dendritic protrusions in cultured hippocampal neurons96, and it binds to the NR1 and NR2B subunits of NMDA receptors, thus providing a cytoskeletal bridge between NMDA receptors and actin. However, its association with NR1 can be competitively displaced from by Ca2+/calmodulin, and it may thus dissociate from the NMDA receptor as a result of Ca2+ influx into the postsynaptic terminal97. Finally a-actinin is also linked to AMPA receptors via the reversion-induced LIM protein RIL, and participates in the regulation of AMPA receptor trafficking within spines98.

IRSp53 not only interacts with Shank, but also with PSD-95 and PSD-93, and these interactions are required for its spine localization: its overexpression in cultured neurons increases the density of dendritic spines, while its siRNAmediated knockdown reduces spine density, length and width. The overexpression of IRSp53 with a point mutation in the SH3 domain (where WAVE2 binds) reduces spine density and size, thus suggesting that IRSp53 plays a role in linking PSD-95 to activated Rac1/Cdc42 and downstream effectors of actin regulation in

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