DYNAMIN, ENDOCYTOSIS AND INTRACELLULAR SIGNALING

Dynamin is a neuronal phosphoprotein and a GTPase enzyme which mediate s late stages of endocytosis in both neural and non-neural cells. Curr ent knowledge about dynamin is reviewed with particular emphasis on it s structure and regulation with respect to phosphorylation, protein-pr otein interactions and phospholipid binding. The major themes are the biochemical regulation of dynamin, its effects on dynamin's GTPase act ivity and how this might relate to assembling the 'fission ring' that brings about vesicle retrieval. Dynamin I is an isoform of the enzyme primarily located in the central and peripheral nervous systems, where it is enriched in areas of abundant synaptic contacts. Dynamin I unde rgoes protein-protein interactions via its proline-rich domain at the C-terminus and these can elevate its N-terminal GTPase activity. Dynam in I interacts with multiple proteins in the nerve terminal, including SH3 domain-containing proteins such as amphiphysin and potentially wi th other proteins such as beta gamma subunits. These regulate its role in endocytosis by targeting dynamin I to specific subcellular locatio ns of retrieval. Dynamin I is phosphorylated in vivo by PKC and dephos phorylated on depolarization and calcium influx into nerve terminals i n parallel with the coupled events of exocytosis and endocytosis. In l ate stages of synaptic vesicle retrieval dynamin I undergoes stimulate d assembly into a collar, or fission ring, that surrounds the neck of recycling synaptic vesicles. Activation of GTP hydrolysis probably the n generates the free synaptic vesicle, which can be refilled with neur otransmitters. This targeting and assembly may involve sequential step s including recruitment of AP-2 to synaptotagmin on the synaptic vesic le, and recruitment of amphiphysin, dynamin I, and synaptojanin. In ad dition to synaptic vesicle retrieval, dynamin has been associated with intracellular events mediated by growth factor receptors, insulin rec eptors and the beta-adrenergic receptor. This is likely to reflect tar geting of these receptors for endocytosis soon after their activation. However, does it also suggest a broader role for dynamin in other asp ects of intracellular signalling pathways?