An isoform of Kalirin, a brain-specific GDP/GTP exchange factor, is enriched in the postsynaptic density fraction

Communication between membranes and the actin cytoskeleton is an important aspect of neuronal function, Regulators of actin cytoskeletal dynamics incl ude the Rho-like small GTP-binding proteins and their exchange factors. Kal irin is a brain-specific protein, first identified through its interaction with peptidylglycine alpha-amidating monooxygenase. In this study, we clone d rat Kalirin-7, a 7-kilobase mRNA form of Kalirin, Kalirin-7 contains nine spectrin-like repeats, a Dbl homology domain, and a pleckstrin homology do main. We found that the majority of Kalirin-7 protein is associated with sy naptosomal membranes, but a fraction is cytosolic, We also detected higher molecular weight Kalirin proteins. In rat cerebral cortex, Kalirin-7 is hig hly enriched in the postsynaptic density fraction. In primary cultures of n eurons, Kalirin-7 is detected in spine-like structures, while other forms o f Kalirin are visualized in the cell soma and throughout the neurites, Hali rin-7 and its DM homology-pleckstrin homology domain induce formation of la mellipodia and membrane ruffling, when transiently expressed in fibroblasts , indicative of Rad activation. Using Rad, the DM homology-pleckstrin homol ogy domain catalyzed the in vitro exchange of bound GDP with GTP, Kalirin-7 is the first guanine-nucleotide exchange factor identified in the postsyna ptic density, where it is positioned optimally to regulate signal transduct ion pathways connecting membrane proteins and the actin cytoskeleton.