Developmental role of neuronal calcium sensors

Too much of a good thing - the harmful effects of calcium

The flow of calcium ions in and out of nerve cells is central to the complex workings of the brain. Calcium is necessary for the release of neurotransmitter vesicles at synaptic contacts to allow the propagation of signals between neurons. Storing memories requires the formation and strengthening of connections; this remodelling is founded upon the influx of calcium through membrane receptor channels. Intracellular calcium modulates a host of signalling pathways which must be tightly controlled in space and time to maintain the health of the neuron. Although calcium is central to neuronal function, elevated levels are extremely harmful due to excitotoxic activation of signalling pathways, membrane channels and enzymes which combine to overwhelm and ultimately kill the cell. This is particularly important within the central nervous system because of the extremely limited capacity for renewal and replacement of neurons. Failure to maintain neuronal calcium homeostasis is associated with chronic neurodegenerative conditions such as motor neuron disease (MND) or Alzheimer Disease and acute insults such as stroke.

No rest for the oculomotor system

One of the features of the oculomotor system is that it is frequently spared in degenerative conditions such as motor neuron disease and muscular dystrophy. The reasons for this are uncertain but it has been suggested that this is due to the particular demands placed upon the nerves and muscles that control eye movements. They are never at rest. Simply reading this page requires sophisticated eye movements to scan the page without the letters blurring. This latter point is fundamental to why our oculomotor system is so essential and why we take it for granted. Even if you try and hold your head still, it will move slightly as you breathe or your body flexes; if your eyes were rigidly fixed then the image of the world captured on the retina at the back of your eyeball would also move slightly and hence become blurred. The fact that we see a steady, consistent, single image of the world around us at all times (barring injury or inebriation) is testament to the exquisite control of our oculomotor system. Their work is not done when we sleep - the eyes do not stop moving, most notably during REM (Rapid Eye Movement) phases. Each one of these tiny adjustments requires the nerves to conduct a signal and the muscles to contract in response and each of these involves calcium flowing in and out of cells. As described above, this places a great stress on the cells involved and it may be that oculomotor nerves and muscles have evolved mechanisms to protect themselves from this relentless flow of calcium.

Neuronal calcium sensors - the master switch?

Calcium binding proteins (CaBPs) are thought to act like sponges and buffer neuronal calcium flux thereby protecting against excitotoxic damage and degeneration. High levels of CaBPs are found in oculomotor neurons (and a few other types of neuron) that are resistance to MND. This provides circumstantial evidence for CaBPs being the source of protection against degeneration however there is little direct evidence that this can be harnessed. Given our expertise in the oculomotor system, this was an intriguing problem and one that we were keen to tackle. It was whilst researching exactly which CaBPs are produced by oculomotor neurons that we serendipitously came across the neuronal calcium sensors (NCS).

Neuronal calcium sensors were a particularly exciting proposition because rather than being a passive sink, they respond to binding calcium by rapidly associating with intracellular membranes where they can potentially direct the assembly and output of signalling complexes. Being able to control this translocation offers the possibility of triggering specific subcellular changes to promote cell survival following excess calcium accumulation and could be used therapeutically to prevent or reverse the effects of calcium dysregulation. For CaBPs in general, the prevailing view is that higher protein levels provide a greater buffering capacity. However, in the case of neuronal calcium sensors, it is equally possible that elevated calcium triggers these proteins to activate inappropriate and ultimately harmful signalling cascades.

Calcium can be harmful to neurons...?!

Neuronal calcium sensor signalling

A role in guiding neurons?

A lot of work has been done to investigate the general function of neuronal calcium sensors (NCS) in cell lines and to begin to address their role in mature neurons We examined the expression of various NCS genes during the early stages of nervous system development. As a family of genes they have very similar DNA sequences and therefore the proteins produced have equally, if not more, similar compositions. This redundancy is often taken to imply that the proteins are very important and that they have evolved this way so that accidental mutations in one of them can be compensated by one of its relations to prevent loss of function. However, we have found that although there is some overlap, specific NCS are restricted to separate neuronal populations. By genetically altering the amount of NCS protein produced by neurons we are investigating their role in the early development of particular types of neuron. Understanding the signalling pathways in which they operate to wire up the nervous system will provide crucial information to help decipher how they may be used to tackle neurodegeneration when that wiring begins to unravel.

Other research topics: