Membrane fusion at the synapse: Janus faced synaptotagmin-1 helps to keep the fast pace

October 30, 2008

Imagine a bathtub with two soap bubbles colliding but never fusing. Then you add detergent, and the surface of the water goes flat as the walls of the bubbles collapse and merge.

Dr. Christian Rosenmund, professor of neuroscience and molecular and human genetics at Baylor College of Medicine, and graduate student Mingshan Xue use that analogy to describe the action of synaptotagmin-1, which acts to catalyze the fusion of the membranes of tiny neurotransmitter-filled bubbles called vesicles with the wall membrane of a neuron. This action allows signals to flow between neurons.

In a report in the current issue of Nature Structural and Molecular Biology, Rosenmund, Xue and colleagues from The University of Texas Southwestern Medical School at Dallas turn the notion of how synaptotagmin-1 accomplishes this task upside down, making an important step forward in understanding how synaptotagmin-1 accomplishes this task.

In fact, said Xue, bringing the two membranes together involves both the top and bottom of a key domain of the protein. He demonstrated this in a series of elegant experiments that validated the importance of the bottom of the domain.

"We are looking at the molecular mechanism of synaptic transmission or how neurons communicate in the brain," said Xue.

Previously, experts had thought that only the top areas of the so-called C2B domain of synaptotagmin-1 were involved in facilitating fast neurotransmitter release.

When the neuron is in a pre-synapse phase, it explodes in electrical activity that opens a channel allowing positively charged calcium ions to go to the balloon-shaped vesicles inside the presynapse to trigger the release of neurotransmitter. Transferring neurotransmitters from one neuron to another requires the fusion of the vesicle's membrane with its host plasma membrane. This allows the neurotransmitter to diffuse to the postsynaptic part of the synapse.

Neurons send and receive information via two structures that make up the synapse. On the sending site, the electrical activity of the neuron needs to be rapidly converted into a chemical signal via release of a hormone or neurotransmitter.

The trigger for this is the flux of calcium ions into the nerve terminal. The receiving neuron on the other site of the synapse detects the neurotransmitter via receptors and converts it again into electrical activity.

It takes no more than 1/1,000th of a second for this to occur. Neuroscientists are not only fascinated by this astonishing speed, but they also recognize that disturbing the speed of synaptic transmission has deleterious consequences on brain function and can lead to various diseases of the nervous system including schizophrenia, depression, Parkinson's disease, epilepsy and Alzheimer's disease.

Rosenmund and colleagues found that synaptotagmin-1 plays an important role in maintaining this speed. Bringing two fusing membranes close enough so that they fuse with each other is a crucial step in the process. The housekeeping machinery that accomplishes this in many biological processes is made up of the so-called SNARE proteins that form protein bundles across vesicle and plasma membranes, hurling the vesicle or balloon-like structure close to the membrane. While this process works very well, it is just too slow for synapses operating in a millisecond.

"That's where synaptotagmin-1 and calcium come into the game," said Rosenmund. "Its C2B domain binds at the top site to calcium ions, allowing the subsequent attachment to of the two membranes."

In their current work, Xue, Rosenmund and colleagues showed that the bottom of the C2B domain is also critical in bringing the membranes of the neuron together with the vesicle's membrane, allowing the release of neurotransmitter.

"Nature invented SNARE first to help the process," said Xue. "But that did not take into account the high demand of the neurons. When the calcium comes, we need a fast neurotransmitter release. Nature then invented synaptotagmin-1 to respond to the calcium. It's a trigger. The molecule is turned on and interacts with both membranes."

Baylor College of Medicine

Neurotransmitters and Neuromodulators: Handbook of Receptors and Biological Effects
by Oliver von Bohlen und Halbach (Author), Rolf Dermietzel (Author)

A complete update of the highly acclaimed handbook with data on all neurotransmitters and the majority of neuromodulators. The coverage is now even more comprehensive, with 15% more entries on neuropeptides, "classic" neurotransmitters and related substances in a clear, alphabetical format. The methodological section has been expanded by 50% and now includes color figures, plus new chapters on genomics, proteomics, databases, microarrays, MALDI-TOF, neutrophins, FGF, endocannabinoids and neuroimaging. The text provides clearly structured information on the biosynthesis and degradation, localization, receptors, signal transduction pathways, and biological effects in the central nervous system, with all substances uniformly treated for an easy comparison of data. Furthermore, introductory...

The Neurotransmitter Era in Neuropsychopharmacology
by Thomas A. Ban (Author), Ronaldo Ucha Udabe (Editor)

This book consists of a collection of reviews prepared by basic scientists and clinicians involved in different areas of neuropsychopharmacology. The book focuses on the neurotransmitter era in neuropsychopharmacology.

Neurotransmitter Transporters, Volume 296 (Methods in Enzymology)
by John N. Abelson (Editor), Melvin I. Simon (Editor), Susan G. Amara (Editor)

General Description of the Series:
Neurotransmitter Transporters focuses on biochemical, electrophysiological, pharmacological, molecular, and cell biological approaches used to study neurotransmitter transport systems. The articles provide detailed descriptions of procedures that should enable the reader to understand how they are accomplished and to repeat or adapt them for their own experimental needs. This book is the first to focus on methods that have been the basis for the rapid development of this area.
General Description of the Series:
The critically acclaimed laboratory standard for more than forty years, Methods in Enzymology is one of the most highly respected publications in the field of biochemistry. Since 1955, each volume has been eagerly awaited, frequently...

Heal with Amino Acids and Nutrients. Survive Stress, Pain, Anxiety, Depression, & More Without Drugs--What to Use and When
by Pain & Stress Publications

Amino acids are the medicines of the 21st century. Your brain and body cannot function without amino acids. Amino acids have the healing power to help you feel better, think better, and stay healthy.

Learn the natural power of amino acids to:

Control the anxiety "stop switch"/ Enhance brain function, memory, and concentration/ Function as a muscle relaxant, and pain reliever/ Stop cravings for alcohol, sugar, and carbohydrates/ Create neurotransmitters for brain communication/ Stop hyperactive, ADD, and aggressive behavior/ Enhance sexual pleasure/ Create needed serotonin for smooth brain function/ Replace toxic drugs.

Find out why you have amino acid deficiencies and which you can use to find the answers you need.

Secrets to Controlling your Weight, Cravings and Mood: Understand the biochemistry of neurotransmitters and how they determine our weight and mood
by Maria Emmerich (Author)

Before Maria’s passion for nutrition, she had a passion for donuts. She was an athlete and thought she could get away with eating what she wanted, as long as she worked out. NOT TRUE. Even though she ate enough calories, she was starving herself, specifically, she was starving her brain. Her stomach was filled with “substance” but her brain kept telling her to eat; our bodies are smart, they make us crave certain nutrients we need. For 90% of dieters, a deficiency in one of four essential brain chemicals can cause weight gain, fatigue, and stress. The solution to losing weight doesn’t lie in deprivation diets; it lies in balancing our neurotransmitters. 1. Serotonin influences appetite. 2. GABA curbs emotional eating 3. Acetylcholine regulates fat storage 4. Dopamine controls...

The War of the Soups and the Sparks: The Discovery of Neurotransmitters and the Dispute Over How Nerves Communicate
by Elliot Valenstein (Author)

Like the cracking of the genetic code and the creation of the atomic bomb, the discovery of how the brain's neurons work is one of the fundamental scientific developments of the twentieth century. The discovery of neurotransmitters revolutionized the way we think about the brain and what it means to be human yet few people know how they were discovered, the scientists involved, or the fierce controversy about whether they even existed. The War of the Soups and the Sparks tells the saga of the dispute between the pharmacologists, who had uncovered the first evidence that nerves communicate by releasing chemicals, and the neurophysiologists, experts on the nervous system, who dismissed the evidence and remained committed to electrical explanations.The protagonists of this story are Otto...

Co-Existence and Co-Release of Classical Neurotransmitters: Ex uno plures
by Rafael Gutierrez (Editor)

Dale's Principle postulated that a neuron functions as a metabolic unit, whereby a process occurring in the cell can influence all of the compartments of that given neuron. This was unfortunately transformed in the literature to a principle stating that “a single cell releases only one neurotransmitter”. Until recently, this has influenced many neuroscientists to consider with skepticism the idea that classical neurotransmitters could be co-released from neurons. It is now clear that the “one neuron, one neurotransmitter” postulate is the exception rather than the rule. The aim of this book is to gather the available evidence, provided by the authors that have discovered and studied the co-existence or co-release of several pairs of neurotransmitters, in several neural networks....

Nutrition and Neurotransmitters: The Nutrient Bases of Behavior (Prentice Hall advanced reference series)
by Michael D. Chafetz (Author)

Neurotransmitters, Drugs and Brain Function
by Roy Webster (Editor)

Neurotransmitters, Drugs and Brain Function aims to link basic aspects of the activity of neurotransmitters at the receptor and synaptic level with their role in normal brain function, disease states, and drug action. Thus, the material considers to what extent our knowledge of the central synaptic action of certain drugs can explain their possible roles in the cause of diseases and in the modes of action of drugs effective in those conditions.

It offers a working explanation of drug and neurotransmitter action in CNS function, with a clear, comprehensive, and challenging style of writing. The authors review the chemical basis for drugs and the conditions they treat. It also, includes numerous illustrations and schematic diagrams.

Neurotransmitter Transporters: Structure, Function, and Regulation (Contemporary Neuroscience)
by Maarten E. A. Reith (Editor)

Maarten Reith and his contributors fully update all the material in his widely acclaimed first edition, expanding it to include the important progress made in characterizing the structure, function, regulation, and physiological relevance of each transporter. The new material includes discussions of gene organization and the relationship of polymorphisms of monoamine transporters with a variety of diseases, transgenic animals carrying altered genes for plasma membrane monoamine transporters, and the regulation of transporters by trafficking in relation to their phosphorylation state. Also addressed are transporter imaging techniques that allow in vivo measurement in men and animals, chimera and site-directed mutagenesis of transporters, and transporter electrophysiology. Neurotransmitter...