News Release

Small G-Proteins Make A Big Difference -- Nerve Cell Signalling Is Regulated By Arf-GTPases And Their Activators

Peer-Reviewed Publication

Max-Planck-Gesellschaft



Figure: The msec7-1/Arf6-system regulates the synaptic vesicle supply. At the synapse, synaptic vesicles cycle between an early endosomal compartment and the synaptic plasma membrane. A large number of proteins regulates the various fusion, fission and transport reactions that constitute the life cycle of synaptic vesicles. Vesicles are generated by budding from early endosomes and are loaded with neurotransmitter (NT). After a translocation process, they dock at the active zone and mature to a fusion competent state. In response to activation and a concomitant rise in the intracellular calcium concentration, vesicles fuse with the plasma membrane and release their content. Vesicular protein and lipid components are then retrieved by endocytosis and recycled via early endosomes (in addition, direct recycling occurs which bypasses the endosomal intermediate). The msec7-1/Arf6-system is thought to increase the number of release-competent vesicles in the synapse by stimulating vesicle translocation to the active zone.

Full size image available through contact at http://www.mpg.de/news99/news05g_99.jpg

Researchers at the Max Planck Institutes for Biophysical Chemistry and for Experimental Medicine in Göttingen/Germany discovered a new regulatory process through which nerve cells modulate the release of neurotransmitter in the brain (Proc. Natl. Acad. Sci. U.S.A. 96, 1094-1099; Feb. 2, 1999).

Information in the brain is transmitted at synapses which are specialized contact zones between a sending and a receiving nerve cell. When stimulated, the sending nerve cell releases signalling molecules. These so called neurotransmitters diffuse to the receiving nerve cell where they activate surface receptors that in turn change the physiological state of the receiving cell and thereby transmit the synaptic signal.

Transmitter release at synapses is a complex process. It involves a large number of proteins which regulate the turnover of synaptic vesicles, small membranous intracellular organelles that store neurotransmitter and release it upon stimulation by fusing with the cell membrane. In a nerve cell, synaptic vesicles pass through a sophisticated cycle of fusion and budding reactions, and the efficiency of these reactions determines the vesicle supply that is ready for transmitter release at any moment in time.

Uri Ashery and Volker Scheuss in the laboratory of Jens Rettig at the Max Planck Institute for Biophysical Chemistry, Göttingen/Germany, used a new method to identify two novel regulators of the synaptic vesicle cycle. In collaboration with Henriette Koch and Nils Brose, head of a research group at the Max Planck Institute for Experimental Medicine in Göttingen/Germany, they expressed the protein msec7-1 in neuromuscular synapses of Xenopus frogs. msec7-1 is an activator of members of the Arf-family of small GTPases. Both msec7-1 and Arfs are very prominent regulators of membrane transport in the Golgi apparatus of all cells in the body. The Göttingen group discovered that the msec7/Arf-system plays an as yet unrecognized role in the synaptic vesicle cycle, where activation of Arf6 by msec7-1 leads to dramatic increases in the synaptic vesicle supply at synapses.

The finding adds a completely novel regulatory process to our understanding of synaptic transmission in the brain, says Rettig. Indeed, while research on msec7-1 and Arfs has boomed during the past few years, it concentrated on intracellular membrane traffic in the Golgi apparatus. Nobody had the proteins on their list of possible synaptic players.

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Contact: Jens Rettig
Max Planck Institute for Biophysical Chemistry,
Department of Membrane Biophysics
Göttingen/Germany
Phone: 49-551-201-1692
Fax: 49-551-201-1688

Contact: Nils Brose
Max Planck Institute for Experimental Medicine,
Laboratory for Molecular Neurobiology
Göttingen/Germany
Phone: 49-551-3899-725
Fax: 49-551-3899-753



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