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  • Jan Clementson

Nicotinic Acetylcholine Receptors: How infections can impact nerve transmission

Emerging from the recent covid-19 pandemic research is an awareness of a key mechanism of action interlinking the immune and nervous systems and hence the biochemical and bioelectrical aspects of the body. Central to this mechanism are a group of proteins that play crucial roles in the functioning of the nervous system. These proteins are called nicotinic acetylcholine receptors (nAChRs). This blog seeks to explore how infections and inflammation negatively impact the nervous system via this mechansim leading to health conditions, whilst also identifying foods and other therapeutic agents that can positively impact these receptors leading to better health outcomes.


What Are Nicotinic Acetylcholine Receptors?


The nAChRs play a crucial role in nervous system function through their mediating actions of a key neurotransmitter (nerve messenger) called acetylcholine. They are named after their affinity for nicotine (a substance found in tobacco and certain plant foods) and acetylcholine. These proteins are embedded in cell membranes and are a type of ligand-gated ion channel.............. meaning they open to allow ions (charged minerals) to pass through the cell membrane in response to the binding of a chemical messenger, in this case, acetylcholine. They are found in various locations throughout the body, including the central and peripheral nervous systems, and play a pivotal role in neurotransmission.


Key Functions of nAChRs


Neurotransmission (Nerve Transmission)

The primary role of nAChRs is to facilitate fast transmission of electrical signals between neurons (nerve cells). Neurons cannot communicate with each other directly as there are gaps between nerve cells. Instead, electrical signals stimulate chemical messengers (neurotransmitters) to bridge the gap and communicate with the next neuron. Acetylcholine is one such neurotransmitter. It binds to nicotinic-acetylcholine receptors in the gap junctions (synapses) to trigger an influx of ions (charged minerals) at the next neuron to transmit the electrical signal. See the video below for a better understanding.




Muscle Contraction

In the peripheral nervous system, particularly at the neuromuscular junction, nAChRs are crucial for translating neural signals into muscle movements through muscle contraction. When acetylcholine is released from motor neurons, it binds to nAChRs on muscle cells, causing these cells to contract. This process is vital for voluntary movements and overall motor coordination.


Cognitive Function

In the brain, nAChRs are involved in cognitive processes such as learning and memory. They are found in various brain regions, including the hippocampus and cortex, where they modulate the release of other neurotransmitters like dopamine and glutamate, influencing neuronal plasticity (ability of synapses to strengthen or weaken over time) and cognitive performance.


Autonomic Nervous System

nAChRs also play a role in the autonomic nervous system, regulating involuntary functions such as heart rate, digestion, and respiratory rate. They mediate synaptic transmission in both sympathetic (stress) and parasympathetic (relaxation) nervous system pathways.



Anti-Inflammatory Pathway Mediation by nAChRs


nACHRs have now also been shown to play a central anti-inflammatory role via a neural mechanism where the vagus nerve (anti-stress) modulates immune responses to control inflammation via nAChRs expressed on immune cells. Activation of nAChRs on macrophages (specific immune cells) inhibits the production of pro-inflammatory cytokiness (specific immune cells) to reduce inflammation. This pathway has therapeutic potential in conditions with excessive inflammation such as infammatory bowel disease or rheumatioid arthriitis. Modulating nAChRs could proive a novel approach to treating these diseases by dampening the inflammatory response.


Factors Impacting nAChR Function


The function and expression of nAChRs can be influenced by various factors. These include genetic variations, environmental factors - such as chronic nicotine exposure from smoking, toxins, chronic stress and dietary factors - pharmacological agents, and disease states. This includes inflammatory conditions and infections which can modulate nACHR activity through the immune system's interactions with the nervous system.


Mechanisms of Infection Impact on nAChRs


Infections can influence the function and expression of nAChRs through various mechanisms, impacting both the central nervous system (CNS) and peripheral tissues. Here are some key mechanisms showing how infections can impact nAChRs:


  1. Direct Viral or Bacterial Interaction: - Certain pathogens can directly bind to nAChRs or interact with them, altering their function.

  2. Inflammatory Cytokine Release - Infections often lead to the release of inflammatory cytokines, which can modulate nAChR expression and function

  3. Neuroinflammation - Infections of the CNS can cause neuroinflammation, leading to changes in nAChR expression and signaling pathways.

  4. Immune Cell Modulation - Pathogens can affect immune cells expressing nAChRs, influencing the cholinergic anti-inflammatory pathway.



Viral Impact on nAChRs


Viruses can affect nAChRs through direct and indirect mechanisms, potentially altering their function and contributing to various disease processes. HIV was found to bind directly to these receptors, whilst other viral proteins have been implicated in mimicing acetylchloine thereby altering nACHR signaling pathways. Viral infections often trigger robust inflammatory responses, leading to the release of cytokines and other inflammatory mediators, which affect nAChR expression and function. They can also cause neuroinflammation, disrupting the normal functioning of nAChRs in the brain and peripheral nervous system, potentially leading to neurological symptoms such as cognitive impairment, mood disorders, and neuropathic pain - such as with the Herpes simplex virus. Research on this topic is ongoing.


COVID-19 and nAChRs


There has been much reserach and controversy over the last few years into the mechanism of action of Covid-19. The nAChRs were identified in the early stages of the pandemic as a potiential target and led to a wealth of research in this area. This great 2023 paper delves into the mechanisms of action and suggests that the nACHRs are indeed the targets for the covid spike protein and, as such, they activate the nAChRs. This understanding opens up potential new therapeutics that target these receptors.



Specific Impacts of Mould Infections


The impact of mould infections on nAChRs is not as extensively documented as other types of infections, but there is some evidence suggesting that mycotoxins produced by moulds can affect nAChRs. Mould exposure can trigger inflammatory responses in the body, which might indirectly impact nACHR activity through the release of inflammatory cytokines. Moreover, macrophages (immune cells) have been found to respond to mould mycotoxins by activating a specific immune pathway (capase 1), which in turn has been found to activate the nAChRs on the macrophages. Mycotoxin research on health is more in its infancy but is subject to ongoing area of research that could help to clarify the mechanisms of action.



Other Clinical Manifestations


Given their widespread distribution and pivotal roles of nAChRs, dysfunctions in these receptors are implicated in other conditions over and above infections, these include several neurological and psychiatric conditions:


  • Myasthenia Gravis -  An autoimmune disease where antibodies attack nAChRs at the neuromuscular junction, leading to muscle weakness.

  • Alzheimer's Disease -  Altered nAChR function is linked to cognitive decline seen in Alzheimer's, making these receptors targets for therapeutic interventions.

  • Parkinson's Disease - Neurodegenerative disorder affecting motor functions. Dysfunctional nAChRs exacerbate symptoms.

  • Epilepsy - Recurrent seizures resulting from excessive neuronal acctivity. Altered nAChR function can disrupt this balance, leading to hyperexcitability and seizures.

  • Schizophrenia - Severe psychiatric disorder characterized by hallucinations, delusions, and cognitive impairments. Altered nAChR expression affects cognitive processes and sensory processing.

  • Attention Deficit Hyperactivity Disorder (ADHD) - Marked by inattention, hyperactivity, and impulsivity. Dysregulated cholinergic signaling, involving nAChRs, is implicated in ADHD.

  • Austisic Spectrum Disorders (ASD) - a complex of neurodevleopment diseases that include impaired social interaction, delayed and disordered language, repetitive or sterotypic behaviour, restricted range of interests and altered sensory processing. New studies now also linking these disorders with dysfunctional nAChR and reduced acetylcholine signalling.

  • Meniere's Disease - Inner ear disorder causing dizziness, vertigo, tinnitus and hearing loss. nAChRs, found to play a key part of inner ear pathophysiology. Emerging evidence of the linkage in this condition will be explored in a separate blog.


As the research in this area grows, the list of conditions affected by dyfunctional nAChRs are likely to grow.



Therapeutic Considerations


Nicotine Products

We have seen that nicotine has great affinity for the nAChRs and that short-term use can stimulate these receptors. Using nicotine products - patches, gums, lozenges - for short-term therapeutic use may be a potential short-term strategy for activiating these receptors. And this is the basis of the ground-breaking research by Dr Bryan Ardis into using nicotine products to combat the symptoms of COVID-19, which is known to affect these receptors. However, chronic use of nicotine products can cause desensitisaiton of the nAChRs, which would then negate the reason for using those products. Also, be aware that some people may be sensitive to nicotine and that it may interact with certain medications. Always check with your healthcare provider before use if you are on any medications or are concerned. These products should be used with caution.


Nicotine in Foods

Nicotine traditionally comes from the tobacco plant - it is a plant molecule. And this same plant molecule is found in other plants too! A fact that is not commonly known. The nightshade vegetables - potatoes, tomatoes, aubergines, bell and chilli peppers - are especially high in nicotine, although not as high as tobacco. Studies have shown that nicotine is created in the roots of the nightshade plants when two chemical compounds – pyridine and pyrrolidine – are joined together before being transported to the leaves. The genes behind this combination exists in all plants, but genetic duplications in the nightshade family are believed to have led to nicotine production. This means that nicotine is already present in our diet in small doses.


Studies estimates that people eat about 1400 ng of nicotine every day in ordinary food. That compares to a single cigarette which contains approximately 12 mg of nicotine – around 18 thousand times more nicotine than a potato, by mass. But only a fraction (<2 mg) of that nicotine is transferred into the smoke of a cigarette. Hence the food content of nicotine is much less than the amount obtained from a cigarette or nicotine product. Eating more of the nightshade vegetables could be a potential strategy for activating the nAChRs. However, be aware that some people are sensitive to the nightsade family vegetables, in which case, avoid these foods.


Nicotinic Acid (Vitamin B3) or Niacin

Nicotinic acid - one of the chemical names of vitamin B3 - bears the same name as the nACHR, so does that also activate the receptors in the same way as nicotine? It seems not. The term "nicotinic" is dervied from its chemical structure, which is similar to nicotine.  However, this similarity does not extend to functional activity of the nACHRs. These receptors respond to the neuortransmitter acetylcholine as well as nicotine. But vitamin B3 does play an important role in the nervous system through various metabolic processes (via certain coenzymes involed in energy production) that support acetylcholine production.


Given the importance of vitamin B3 in nerve transmission, including more foods high in vitaimin B3 could help to support nervous system function and nerve transmisson. High vitamin B3 foods include (in order of levels): chicken, liver, tuna, turkey, salmon, sardines, grassfed beef, mushrooms. avocado, sweet potato, aspargaus.


Acetylcholine Precursors


Acetylcholine is the main activator of the nACHRs. It synthesized from choline and acetyl-CoA (which in turn is synthesised from vitamin B5). Focusing on the precurosrs to acetylcholine is another way to increase activation at the receptor level. Vitamin B5 is fouond in most vegetables - especially broccoli, cabbage, sweet potatoes. mushrooms, whole grains - as well as meat, poulty, eggs, lenitls and nuts. Whilst choline is found in eggs, fish, cauliflower, brussels, nuts and liver. There is a big crossover over of similar foods containing vitamins B3, B5 and choline.



Conclusion


Nicotinic acetylcholine receptors are integral to many physiological processes, from muscle contraction to cognitive functions. Their intricate role in nerve transimission and anti-infllammatory pathways highlights their importance in both health and disease. Factors such as inflammation, infections, auto-antibodies, chronic nicotine exposure, pharmacological agents and genetic mutations can adversely impact their function. Conversely, eating foods that can specifically stimulate the receptors, as well as a broad range of foods that contain nutrients needed for nerve transmission can positively impact receptor function and health.



FURTHER HELP


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