Nitric oxide (NO) is a surprising gaseous neurotransmitter in the brain that also contributes to neurotoxicity when produced in excess.
Nitric Oxide Facts:
- NO is synthesized on demand in neurons and diffuses to activate receptor enzymes rather than binding to membrane receptors.
- As a novel neurotransmitter, NO may mediate memory, plasticity, and retrograde signaling.
- Too much NO can be excitotoxic and lead to neurodegeneration as in stroke.
Source: J Clin Psychiatry
Nitric Oxide: Gas & Neurotransmitter
At first glance, the idea that nitric oxide (NO) is a neurotransmitter seems improbable.
After all, NO is a toxic gas found in automobile exhaust that depletes the ozone layer.
How could this unstable air pollutant also act as a chemical messenger in the brain?
Yet research has proven that neurons do indeed synthesize small amounts of NO to communicate signals across synapses.
This brain gas fulfills many criteria for a neurotransmitter despite its unorthodox features.
However, NO has a dark side – excessive NO production can damage and kill neurons through oxidative stress.
The study of nitric oxide neuroscience remains an evolving field aiming to elucidate its roles in both physiological signaling and neuropathology.
Nitric Oxide Synthesis in Neurons
Certain neurons contain the enzyme nitric oxide synthase (NOS) which generates NO from the amino acid arginine.
NO is synthesized on demand when neurons are activated, rather than being produced in advance and stored in vesicles like classic neurotransmitters.
Moderate NO amounts diffuse directly across the synapse to adjacent cells.
The triggering neurochemicals glutamate and calcium can stimulate neuronal NOS to catalyze NO production.
NO’s Unusual Receptor Mechanism
NO does not bind to specific membrane receptors as other neurotransmitters do.
Rather, NO’s receptor target is an iron molecule contained in the enzyme guanylyl cyclase.
NO binds to the iron and activates guanylyl cyclase, which then synthesizes the second messenger cyclic guanosine monophosphate (cGMP).
Another gaseous neurotransmitter, carbon monoxide, is also involved in regulating cGMP.
Without membrane receptors for NO, the amount of NO produced and its diffusion rate are key determinants of NO signaling effects.
Nitric Oxide: Neurotransmitter Functions
Initial research focused on NO’s role as a vasodilator that relaxes blood vessels and regulates blood flow.
In the brain, NO may primarily function as a retrograde neurotransmitter – a signal released from postsynaptic neurons that diffuses back to presynaptic neurons carrying feedback information.
This could allow NO to induce synaptic plasticity through long-term potentiation (LTP) and long-term depression (LTD), cellular processes believed to underlie learning and memory formation.
NO may also mediate neuronal plasticity in which synapses adapt to gain new roles. However, the exact mechanisms of NO synaptic signaling remain speculative.
Nitric Oxide: Excitotoxicity & Neurodegeneration
Although NO facilitates physiological signaling at low concentrations, excessive NO production can trigger neurotoxicity.
NO is a free radical that can damage DNA, proteins and lipids through oxidative and nitrosative stress.
The immune system harnesses the toxic potential of NO for macrophages to kill tumor cells and microbes.
However, in the brain, NO overproduction may initiate neuronal death cascades seen in stroke and neurodegenerative disorders.
Ischemia during stroke induces excessive calcium influx that hyperactivates NOS to generate toxic NO levels.
Developing pharmacological agents that restrain detrimental NO overproduction could provide a new neuroprotective treatment approach for stroke and related conditions.
History of Nitric Oxide (NO) Neuroscience
- 1987 – NO first identified as an endothelial signaling molecule inducing vasodilation. This discovery led to Nobel Prize in 1998.
- 1989 – Neuronal NOS cloning provides first evidence for NO synthesis in the brain.
- 1990s – NO identified as a neurotransmitter based on its neuronal synthesis, diffusion, and cGMP activation in target cells.
- 1990s – NO neurotoxicity established from macrophage and stroke model research.
- 1990s – Investigations into NO’s roles in memory and plasticity begin. Mechanisms remain unclear.
- Present – Efforts to develop therapeutics targeting detrimental NO overproduction in neuropathology.
Critical Assessment of NO as a Neurotransmitter
NO fulfills certain criteria that support its classification as a novel gaseous neurotransmitter:
- Synthesized in neurons in response to activating signals
- Diffuses directly to target cells at synapse
- Activates receptor enzyme guanylyl cyclase
- Generates second messenger cGMP for intracellular signaling
- Functions regulated by amount of NO produced and distance diffused
However, NO lacks some features of conventional neurotransmitters:
- Not stored in synaptic vesicles and released by exocytosis
- No membrane receptor subtypes specifically activated by NO
- NO itself is a free radical rather than standard organic molecule
So in summary, NO is an unconventional neurotransmitter that follows its own biological rules for production, diffusion, receptor activation, and inactivation.
Lingering Questions about Nitric Oxide in the Brain…
Although NO is clearly a neurotransmitter, major questions remain about its roles in the brain:
- What specific synaptic plasticity and memory mechanisms are mediated by NO?
- Does NO meet the requirements to be classified as a retrograde neurotransmitter?
- Are there undiscovered membrane receptor targets besides cytoplasmic guanylyl cyclase?
- What impact does NO have on neuronal oscillations and network activity?
- Can NOS activity be modulated pharmacologically to optimize NO signaling while preventing overproduction?
Further research on NO neurotransmission promises to provide insights into synaptic communication, neuronal adaptation, excitotoxicity, and opportunities for therapeutic intervention.
This ongoing investigation will clarify how the brain’s toxic fumes are harnessed for physiological signaling while also inflicting damage when produced excessively.
References
- Study: Brain fumes: yes, we have NO brain gas
- Authors: S M Stahl (1998)
