Answer: Nitric oxide (NO) is a gasotransmitter that activates the guanylate cyclase signal transduction pathway.
When we think of neurotransmission, we most often think of some chemical substance such as glutamate or GABA that is produced by the neuron, packaged at the terminal, stored in synaptic vesicles, then released into the synapse via membrane fusion. For most neurotransmitters such as dopamine, serotonin, or norepinephrine, this is how neurons communicate with one another at a chemical synapse.
There are some synapses however that use chemical other than these substances. For example, some neurons communicate using the gaseous neurotransmitter nitric oxide (NO). NO and other gaseous signaling molecules are called gasotransmitters.
Nitric oxide synthesis via NOS.
Neurotransmitters like acetylcholine are synthesized with the action of enzymes like choline acetyltransferase. The synthesis of NO begins with the amino acid arginine. Through the action of the enzyme nitric oxide synthase (NOS), arginine is converted into citrulline and a molecule of NO.
There are three different isoforms of NOS. Endothelial NOS (eNOS) is expressed heavily in endothelial areas, and the NO created by this isoform is important for muscle tone and blood vessel dilation. Inducible NOS (iNOS) is important during the immune response. Neuronal NOS (nNOS) is found in nervous tissue and participates in neuronal signaling.
Nitric oxide is not packaged into synaptic vesicles.
Other classical neurotransmitters like acetylcholine are stored in synaptic vesicles before they are released at the axon terminal. They are loaded into synaptic vesicles by proteins like vesicular acetylcholine transporter (vAChT), which are antiporters that use the chemical gradient of H+ ions moving out of the vesicle to power the transport of ACh into the vesicle. Nitric oxide does not get stored in vesicles. Instead, nitric oxide is synthesized de novo as it is needed.
Nitric oxide receptors are not transmembrane proteins.
Many classical neurotransmitters like acetylcholine are molecules that are cell membrane impermeable. Therefore, for these neurotransmitters to affect cellular excitability, they must activate a transmembrane protein called a receptor. Nitric oxide, however, is a gas, making it able to easily cross the neuronal membrane. NO is capable of activating intracellular receptors, the main receptor being soluble guanylate cycle (sGC).
SGC is an enzyme similar to adenylate cyclase. GC acts at a molecule of GTP to create cyclic GMP, or cGMP. CGMP is an important intracellular signaling molecule. Downstream of CGMP is protein kinase G (PKG), which has phosphorylation targets at certain serine / threonine amino acid residues.
Nitric oxide is capable of modifying synapses in complex ways. For example, at the calyx of Held, a large synapse in the auditory system, NO inhibits a potassium channel. It was also identified that excess nitric oxide can be toxic to some neurons, suggesting that unusual NO signaling may be associated with neurodegenerative disorders like Alzheimer's disease. (Nitric Oxide Can Alter Brain Function)