Monday, May 14, 2012

Protein found that orchestrates neural communication

Our nervous system is an immensely complex network consisting of many individual cells, called neurons, that are connected to each other. There are different types of neurons, including sensors, that catch the required signals for hearing, seeing and feeling things, but also those that control our bodily functions: all of our muscles and organs are ultimately controlled by the central nervous system, of which the brain is ultimately in charge. Keeping everything, either conscious or subconscious, running at the same time requires an incomprehensible amount of communication and structure, still leaving scientists puzzled at its complexity. While we have already identified many individual molecules that play a role in it, scientists from Weill Cornell Medical College have found one that seems to be at the core of neural communication. By elucidating the workings of this powerful protein, we are able to create new therapies to control body functions.

The synapse
Alpha 2 delta protein, as it is known to scientists, functions at a highly specialized part of the neural cell, called the synapse. Here, junctions are formed to allow neurons to communicate with each other, by using specialized molecules called neurotransmitters. Neurons use axons to send signals, and dendrites to accept signals, which is why synapses between two of them are formed by using an axon and a dendrite. Before a neurotransmitter carrying a certain message can be sent across the gap that divides the two neurons, electrical stimulation is necessary, which is where so-called voltage-gated channels come in. They get the cell 'charged' in the right way, allowing for the message to be unleashed.
Opening of voltage-gated calcium channels brings synaptic vesicles containing neurotransmitter to the synapse, delivering their message to receptors on receiving neurons.
Calcium channels
Charging a cell is mostly done by using channels that transport electrically charged molecules in and out of the cell. In the case of neurons, calcium channels, transporting the Ca2+ ion, are used. When a signal needs to be spread to neighbouring neurons, these channels need to open up, allowing flow of ions into the cell, which causes the difference in electrical charge between the inside and outside of the cell to change. This charge 'depolarizes' the cell, allowing for the aforementioned release of neurotransmitter. The alpha 2 delta protein makes sure there are enough Ca2+ channels available at the synapse to let neurons start 'talking'.

Opening the gates
Despite alpha 2 delta's efforts to get calcium channels to the synapse, they still need to open themselves up before a cell can get charged, or, as biologists say it, depolarized. One way to do this, is to activate them by using neurotransmitters, which kind of completes the circle. There are other ways to open up the channels: sometimes this is done in a sort of time-related way, for example to control the pump function of the heart, which requires timely signals. Whatever the reason for opening up the channels, it is necessary to create a small change in electrical charge across the cellular membrane before they open, to create an even bigger electrical spark.
Opening of voltage-gated channels by using a neurotransmitter. The resulting influx of ions into the cell can then result in release of more neurotransmitter. Neurotransmitters can also prevent voltage-gated channels from opening, by reversing the charge.
Controlling communication
It is impossible to send chemical messages to neighbouring neurons without an electrical spark, highlighting why these calcium channels are so important. And because alpha 2 delta controls the number of available calcium channels, it effectively stands at the basis of neural communication. Even though there are many different neurotransmitters that each have their own message and function, they rely on depolarization by calcium channels to push them across the gap to other cells. However, cells also rely on other voltage-gated channels, that make use of sodium and potassium. They work in similar fashion.

There already is a drug available that targets alpha 2 delta: a painkiller called lyrica. It was previously not well understood why the drug works, but the newfound knowledge about alpha 2 delta explains its mechanism of action. By targeting the protein, it can no longer carry out its normal function, reducing calcium channels, and thereby neural signalling. Because pain is also a signal that needs to be processed from sensor to brain, it involves neural communication. Blocking communication between neurons by blocking alpha 2 delta also reduces the possibility to feel pain, hence why lyrica functions as a painkiller.

Novel therapeutics
New approaches that attempt to block certain communication pathways by targeting alpha 2 delta could lead to new treatments for neurological diseases. Because everything is ultimately controlled by the nervous system, there are a lot of ways in which things can go wrong, and therefore a lot of different situations call for altered signalling. The scientists conducting the alpha 2 delta study have shown that it is possible to cut off neural communication by depletion, but by upping the levels of the protein, it is also possible to increase the number of calcium channels: experimental models showed their numbers can be tripled.

Lots of patients could benefit from altered neural communication. However, because the nervous system works with many different neurotransmitters in an immensely complex network, it is hard to modify it properly. By uncovering the workings of a protein that seems to function as some sort of master switch for neural communication, scientists gain a powerful tool to more effectively manipulate the system and bend it to our will in patients suffering from a wide variety of diseases.

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