Interaction between GRIP and Liprin-α/SYD2 Is Required for AMPA Receptor Targeting

GRIP is present at excitatory synapses by immunocyto-Technology chemistry, but GRIP also exists abundantly in nonsynap-Taejon 305-701 tic locations such as in dendritic shafts (where it is asso-Korea ciated with vesicles and microtubules), axons, axon 4 Department of Cell Biology and Anatomy terminals, and cell soma (associated with endoplasmic Summary example, the association of GRIP with intracellular vesi-cles suggests a possible role in protein transport in Interaction with the multi-PDZ protein GRIP is required neurons. for the synaptic targeting of AMPA receptors, but the The liprin-␣ family of proteins (liprin-␣1,-␣2,-␣3, and underlying mechanism is unknown. We show that-␣4) was first identified by their interaction with the LAR GRIP binds to the liprin-␣/SYD2 family of proteins that family of receptor protein tyrosine phosphatases (LAR-interact with LAR receptor protein tyrosine phospha-RPTPs), which includes LAR, PTP␴, and PTP␦ (Pulido tases (LAR-RPTPs) and that are implicated in presyn-constructs that interfere with the GRIP-liprin interac-Serra-Pagè s et al., 1995, 1998). In cultured cell lines, tion disrupt the surface expression and dendritic clus-liprin-␣ colocalizes with LAR-RPTP at focal adhesions, tering of AMPA receptors in cultured neurons. Thus, suggesting a possible role in cell-matrix interactions by mediating the targeting of liprin/GRIP-associated (Serra-Pagè s et al., 1995). proteins, liprin-␣ is important for postsynaptic as well The C. elegans liprin-␣ homolog syd-2 was isolated as presynaptic maturation. in a screen for mutants affecting localization of the syn-aptic vesicle protein synaptobrevin (Zhen and Jin, 1999). Syd-2 mutants display an abnormally diffuse distribution Introduction of presynaptic markers, lengthening of active zones, and impaired synaptic transmission (Zhen and Jin, AMPA-type glutamate receptors mediate excitatory 1999). Zhen and Jin (1999) suggested that SYD-2 might synaptic transmission and are composed of heteromeric function in presynaptic differentiation as a structural combinations of GluR1-4 subunits. The GRIP family of component of active zones and/or as a molecular anchor recruiting other molecules such as LAR-RPTP to the