NOVEL MEMBERS OF THE VESL HOMER FAMILY OF PDZ PROTEINS THAT BIND METABOTROPIC GLUTAMATE RECEPTORS/

Vesl-1S (186 amino acids, also called Homer) is a protein containing E VH1- and PDZ-like domains whose expression in the hippocampus is regul ated during long term potentiation (LTP), one form of synaptic plastic ity thought to underlie memory formation (Kato, A., Ozawa, F., Saitoh, Y., Hirai, K., and Inokuchi, K. (1997) FEBS Lett. 412, 183-189; Brake man, P. R., Lanahan, A. A., O'Brien, R., Roche, K., Barnes, C. A., Hug anir, R. L., and Worley, P. F. (1997) Nature 386, 284-288). Here we re port additional members of the Veal/Homer family of proteins, Vesl-1L and Vesl-2. Vesl-1L (366 amino acids), a splicing variant of Vesl-1S, shares N-terminal 175 amino acids with Vesl-1S and contains additional amino acids at the C terminus. Vesl-2 (354 amino acids) was highly re lated to Vesl-1L in that both contain EVH1- and PDZ-like domains at th e N terminus (86% conservation) and an MCC (mutated in colorectal canc er)-like domain and a leucine zipper at the C terminus. In contrast to vesl-1S, we observed no changes in the levels of vesl-1L and vesl-2 m RNAs during dentate gyrus LTP. All these proteins interacted with meta botropic glutamate receptors (mGluR1 and mGluR5) as well as several hi ppocampal proteins in vitro. Vesl-1L and Vesl-2, but not Vesl-1S, inte racted with each other through the C-terminal portion that was absent in Vesl-1S. Vesl-1L and Vesl-2 may mediate clustering of mGluRs at syn aptic junctions. We propose that Vesl-1S may be involved in the struct ural changes that occur at metabotropic glutamatergic synapses during the maintenance phase of LTP by modulating the redistribution of synap tic components.