Nitric oxide · Grey Matter

Nitric oxide is a gas that neurons make the moment calcium rises inside them and that diffuses freely through membranes to neighbouring cells, where it acts on synapses and on the small blood vessels that bring active tissue its energy.

Nitric oxide. Nitric oxide is a gas that neurons make the moment calcium rises inside them and that diffuses freely through membranes to neighbouring cells, where it acts on synapses and on the small blood vessels that bring active tissue its energy.

It breaks every rule of a classical transmitter. It is not stored or released by exocytosis; it is synthesised on demand by neuronal nitric oxide synthase (nNOS), an enzyme switched on by calcium and calmodulin, often anchored next to NMDA receptors, so it is made when glutamate signalling lets calcium in. Being a small uncharged gas, it crosses membranes in every direction and spreads beyond the synapse that made it, to a sphere of neighbouring cells and vessels, before it decays. Its main receptor is inside the target cell: soluble guanylyl cyclase, which makes the second messenger cyclic GMP.

It can act backwards. Made in the postsynaptic cell, it reaches the presynaptic terminal and has been implicated in some forms of long-term potentiation as a retrograde messenger.

It widens vessels. Nitric oxide relaxes the smooth muscle of arterioles and is one of the signals that couple local activity to increased blood flow.

In excess it harms. During excitotoxicity calcium overload drives nNOS hard, and nitric oxide combines with superoxide into peroxynitrite, a reactive molecule that damages proteins and DNA.

Nitric oxide is a signal that cannot be aimed.

It reaches whatever lies within diffusion range, so it reports where activity is high to every cell and vessel nearby.

Questions: How does a busy patch of cortex get more blood within seconds? Active neurons and astrocytes release signals that relax the smooth muscle of nearby arterioles and the pericytes on capillaries, widening them within a second or two. Nitric oxide from neurons is one of these signals, along with prostaglandins and other messengers triggered by glutamate and by calcium rises in astrocytes. The response is fed forward from signalling itself, often arriving before any shortage of energy, and it delivers more oxygen than the tissue uses, which is why active areas show more oxygenated blood. That surplus of oxygenated blood is what functional MRI detects as the BOLD signal. How can nitric oxide signal without vesicles, receptors on the surface or a synapse? Nitric oxide is a small gas, so it is made at the moment it is needed and leaves the cell by diffusing straight through membranes. Its synthesising enzyme in neurons, nNOS, is activated by calcium and calmodulin and is often anchored next to NMDA receptors, so glutamate signalling that lets calcium in also makes nitric oxide. It spreads to nearby cells in all directions, including back to the presynaptic terminal, and acts on soluble guanylyl cyclase inside them, which makes the second messenger cyclic GMP. The signal cannot be aimed or stored, so it reports the level of local activity to everything within reach until it decays.