Feature: Proteins that make you think

We are quite accustomed to the idea of instantaneous communication with our fellow humans wherever they are in the world, whether to relay an important message, get a job done, check on the kids or start the latest political revolution.

On the other hand, we are not quite so confident when asked exactly how it is that a nerve cell little more than a metre in length can just as instantaneously make our fingers move to send that text or make that phone call as the mood takes us.

Associate Professor Fred Meunier at The University of Queensland (UQ) has spent his research career pondering just this mystery. More specifically, he wants to understand the molecular mechanisms responsible for releasing waves of neurotransmitters from inside nerve cells – a process known as exocytosis – to execute the transmission of neural signals.

To this end, Meunier’s research in the Queensland Brain Institute (QBI) at UQ spans several different research projects, and at the Hunter Cellular Biology meeting, he presented the latest discoveries on one of these aspects involving an enigmatic little protein called Munc18.

While it’s a pivotal element of nervous function, exocytosis is yet to be fully understood. It relies on a series of tightly regulated molecular events that culminate in a burst of neurotransmitter release at the neural synapse.

For this to happen, the neurotransmitters must be parcelled up correctly at the Golgi for delivery to the outer cell membrane, where the two membranes have to fuse for the contents to be finally released.

The membrane docking and fusion step is executed by three fusion proteins called SNAREs (SNAP [Soluble NSF Attachment Protein] Receptor), which come together in a cell-specific manner to form a so-called SNARE complex at the target membrane.

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With the assistance of a few regulatory proteins, this complex drives two membranes to fuse when the time is right so the neurotransmitters can be released into the extracellular space to do their thing.

One of these SNARE-complex regulators is Meunier’s protein of interest, Munc18, which binds specifically to one of the SNARE proteins called syntaxin on its way to the fusion event. Although this binding was demonstrated some years ago, many hours of research since have taught Meunier and the rest of the field one thing, if nothing else: this interaction between Munc18 and syntaxin is complex to say the least.

Multiple roles in exocytosis have been attributed to Munc18, with some gaining more acceptance than others. The bottom line is that exactly how Munc18 has its effects on neural transmission remains cloudy.

A breakthrough in working out what Munc18 might be doing in nerve function came in 2000, when a group in the Netherlands succeeded in making a Munc18-knockout mouse. According to Meunier, this step forward excited the field immensely because neurotransmission in these mice is completely blocked. “It is a pretty amazing effect, and this showed us that Munc18 is definitely critical for the mechanism of exocytosis in neurons.”

Yet, at around the same time, another group added a paradoxical twist to the Munc18 story by showing that it could also impair exocytosis by holding its SNARE-complex binding partner, syntaxin, in a tight bond that prevented it from interacting with any other SNARE proteins, and in turn prevented vesicle fusion.

Since then Meunier has been trying to understand how Munc18 might actually function in exocytosis, given the controversial and seemingly contradictory findings by prominent groups in the field.

“For a long time, this was about as far as we got, with nothing else of major functional significance actually being discovered to complete the puzzle,” Meunier said. “Everyone was just talking around the topic and just hanging out for the next pivotal piece of information.”