Introduction to Cell Receptors
Our physical and mental wellbeing, immune system, ability to cope with stress, are all profoundly affected by the levels of various chemicals, such as neurotransmitters and hormones, floating around our system, whether these are created internally or ingested. Dopamine, serotonin, adrenaline, oxytocin, melatonin to name just a very few.
However, there is something which is possibly more primary than the levels of the chemicals themselves, that is tied to the mechanism by which these chemicals actually affect change.
These chemicals work through attraction and docking on to special sites [proteins] on the surface of cells called "cell receptors". There are very many types of these receptors, each designed to attract a specific chemical to "bind" with it, which then activates a change in the cell function.
For, example dopamine cell receptors attract dopamine molecules to bind with them in order to create change. In fact, there are more types of receptors as there are chemicals, as each chemical may unlock different functions. There are at least five types of cell receptor for dopamine, for example (see below).
The function which is unlocked by a molecule docking with a receptor can be things like excitation - increasing the rate at which the cell sends signals to other cells, or inhibition - silencing signals from the cell, or even cell division or cell death.
An important part of this concept is that the number of active cell receptors is not fixed and can change dramatically over time with stimulus, and changes can occur very quickly. The population of some dopamine cell receptors can change overnight with a bad nights sleep, or can be temporarily increased by ingesting caffeine, for examples.
This is called upregulation and downregulation of the cell receptors.
Importantly, changes in the cell receptor populations can in turn drives changes in insensitivities or sensitivities of the brain and body to the target chemical, through feedback loops. Insulin resistance is an example of this.
Upregulation and downregulation [cell receptor population dynamics] has very profound affects on biological functions, and hence on health and wellbeing, nervous system regulation, susceptibility to infection (immune function), ability to deal with stress, aging.
Cell receptor population dynamics therefore may play a primary role in environmental interactions (nurture) and can profoundly affect biology (nature), and may be the mechanism through which history gets written into the body, such as affects of childhood trauma in later life. Cell receptor population dynamics also provide strong and significant neuroplasticity without the need for new neurons or new synaptic connections/wirings per se, by profoundly affecting the functions and sensitivities of the existing neurons themselves.
Dopamine Cell Receptors and Parkinson’s Disease
It is interesting to note that the standard narrative, that Idiopathic Parkinson’s Disease is the result of the ongoing death of dopamine producing cells in the substantia nigra part of the brain, was arrived at long before the discovery of dopamine cell receptors in 1972, and hence this old story simply doesn’t account for cell receptor dynamics at all. Even more telling, in researching this history, I discovered that the mainstay treatment of PD by l-dopa supplementation was actually struck upon before even dopamine itself was believed to involved in the disease! The full article Levodopa: The Story So Far published in Nature is worth anyone affected by PD reading, but below are some relevant excerpts.
"... he recalled the hostility that greeted him when he presented the results of his key experiments in the late 1950s. The powerful European pharmacological community was locked into a mindset that held dopamine to be no more than a precursor in the biosynthesis of noradrenaline, with no significant biological activity of its own."
"Carlsson presented a paper proposing dopamine as a neurotransmitter and implicating it in Parkinson's disease. He was shocked by the reception. His concepts were wholeheartedly rejected by a traditional community."
"... in 1961.. injected L-DOPA into 20 severely parkinsonian patients. This achieved miraculous, if temporary, effects: for a few hours, their rigid limbs melted into movement."
"... few years... later began trials of an oral form of L-DOPA. His 1968 New England Journal of Medicine paper, reporting a successful two-year study on 28 patients, made the pages of Time magazine. The US Food and Drug Administration approved the drug in 1970."
"Since then, L-DOPA has been the mainstay of Parkinson's disease therapy. Remarkably, no more efficacious drug has yet been developed, although there have been useful attempts. "
"With L-DOPA, a good two-thirds of patients develop mild or severe dyskinesias following several years of therapy, after which the disturbing on–off phenomenon also kicks in. Ideally, L-DOPA would be packaged and delivered in a form that avoided these side effects, but the molecule turned out to be a pharmacologist's nightmare. It looks small and innocent, but has an incompliant chemistry and unhelpful metabolism."
"That no better drug for Parkinson's disease has been found than the first one discovered 40 years ago is a vanishingly rare pharmacological phenomenon. L-DOPA does not slow the inexorable progress of the disease, but if a better way could be found to deliver it then it could keep patients mobile for longer — and delay the need for more radical intervention, such as deep brain stimulation."
Intriguingly, more recently, l-dopa has been found to be a neurotransmitter itself, binding to a cell receptor that is involved in the production of the melanin pigments, and may have a direct effect on PD symptoms, as well as indirectly by being converted to dopamine.
If we now account for the modern knowledge of dopamine cell receptors, than an equally valid narrative for Idiopathic PD would be that, instead of cell death, dopamine cell receptors on the surface of cells in the substantia nigra and other parts of the brain are being downregulated (decreasing in number), resulting in increasing insensitivity to dopamine.
This is a much more hopeful perspective than the degenerative one, since while dead neurons cannot easily be replaced, cell receptors can be upregulated again with the right stimuli.
CELL RECEPTOR INTERNALIZATION
Here we explore one mechanism by which dopamine cell receptors get downregulated. In a recent interview, Prof. Matt Walker gave a very good explanation about a way in which cell receptor populations can change, with the example of caffeine.
"Its at the level of [adenosine] cell receptors that caffeine acts upon."
"As you start to drink more and more coffee, the body and brain changes and builds tolerance. One of the ways the body and brain become tolerant to a drug is via the receptors which the drug binds getting taken away from the surface of the cell, in a process called receptor internalization."
"When there is too much stimulation going on, then if normally the cell would coat its surface with many of these receptors, the cell takes away some of the receptors by sequestering them inside, and therefore downscales its maximum response to caffeine."
"Now you need two cups of coffee, instead of one, to get the same effect."
"When you go cold turkey all of a sudden, the system has equilibrated itself to expecting a certain amount of stimulation, and now the stimulation has been taken away, its got too few receptors, and you get withdrawal syndromes."
"With continued abstinence, the system then starts to get more sensitive again, as the cell starts to repopulate the cell surface with receptors."
This same cell receptor internalization process occurs through usage of many other drugs and pharmaceuticals, which all interact with specific target types of cell receptor as the mechanism of action. However, it is also occurs in response to changes in endogenous chemicals [self-made in the body and brain], as a way of internal regulation via feedback loops.
For example, too much pleasure or thrill seeking stimulation can cause adrenaline receptor internalization, leading to ever more extreme forms of thrill seeking to get an effect, blunting responses to normal levels of pleasure.
Moderation in all things seems key, and if we don't moderate or our environment doesn't moderate, the body's wisdom may enforce moderation through cell receptor internalization.
DOPAMINE CELL RECEPTORS
There are several types of dopamine cell receptors, proteins that can appear on the surface of cells which attract dopamine molecules, switching on or off functions of the cell when the dopamine molecule docks onto the cell receptor site. These include:
D1: memory, attention, impulse control, regulation of renal function, locomotion;
D2: locomotion, attention, sleep, memory, learning;
D3: cognition, impulse control, attention, sleep;
D4: cognition, impulse control, attention, sleep;
D5: decision making, cognition, attention, renin secretion.
So a single chemical, dopamine, can illicit different types of changes to the body and brain through interacting with different types of dopamine receptor.
These are grouped into two themes - D1 type {D1 and D5}, and D2 type {the rest}. The D1 types are excitatory or stimulatory when activated by a dopamine molecule docking, whereas the D2 type are inhibitory of what the D1 type stimulate, thus having balancing effects. Prof. Andrew Huberman divides them into the "go" and "no go" circuits, thus D1 facilitates action, whereas D2 suppresses action.
Dopamine cell receptors are widespread through the body and the brain, not only in the nervous system, but also in the gut, cardio-pulmonary system, kidney and retina.
The populations of dopamine cell receptors appearing on the surface of cells can change dramatically and quite quickly, altering the body's response and sensitivity to dopamine. This can occur through cell receptor internalization processes discussed previously, where receptors are taken into the cell and hidden from the outside. If only specific types of dopamine receptor are affected, this will also alter the delicate "go/no go" balance.
For example, antipsychotic drugs can upregulate or increase the number of D2 receptors, which can cause significant dyskinesia - uncontrolled flailing of the limbs, wobbling of the head, wriggling and writhing movements.
On the other hand, addictive substances can downregulate D2 receptor quantity, resulting in tolerance to the substance, and the need for increasing amounts to get the same high. Food addiction can also decrease dopamine receptors. Cocaine upregulates D3 receptors. Long-term iodine deficiency appears linked to abnormalities in the dopaminergic system that include an increased number of dopamine receptors.
CELL RECEPTOR AGONISTS AND ANTAGONISTS
Cell receptors which attract a specific endogenous chemical to dock with it and activate a cellular response, can also be activated by exogenous chemicals that are similar enough in structure to also fit with the receptor. We have already seen one example of this: caffeine is an exogenous substance which is attracted to natural adenosine cell receptors.
Exogenous chemicals which bind to a cell receptor can either be "agonists", activating the biological response of the cell, more or less the same as if the natural endogenous substance itself had docked with the cell receptor, or "antagonists" which bind to the receptor without activating the biological response, yet blocking the site from binding to the intended target, which is why some drugs are known as "blockers", e.g. beta blockers.
The use of these terms is peculiar given the biological application: agonist from the Greek for contestant, champion, rival; antagonist from the Greek for opponent, competitor, villain, enemy, rival. Indeed, agonists and antagonists can compete with target endogenous substances, and with each other, for cell receptor sites.
Most pharmaceuticals, herbal remedies and natural supplements which are known to have physiological affect typically work through being agonists or antagonists of specific cell receptor types. Plants and fungi have co-evolved with animals to elicit specific reactions on ingestion through interacting with cell receptors.
Some examples:
caffeine is antagonistic, reversibly blocking the action of adenosine on its receptors and consequently prevents the onset of drowsiness induced by adenosine;
morphine mimics (agonizes) the actions of endorphins at μ-opioid receptors throughout the central nervous system;
nicotine is an agonist of nicotinic acetylcholine receptors.
In terms of dopamine receptors, dopamine agonist drugs such as ropinirole and pramipexole bind and activate the D2-type "no go" dopamine receptors, and unlike dopamine itself, can cross the blood-brain barrier. These drugs are notorious for causing compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviours.
Apomorphine is a non-selective dopamine agonist which activates both the D1-type and D2-type dopamine cell receptors. It also acts as an antagonist of 5-HT2 and α-adrenergic receptors with high affinity. Apomorphine has been used to relieve anxiety and craving in alcoholics, an emetic (to induce vomiting), and more recently in treating erectile dysfunction, as well as for Parkinson's Disease. It is injected sub-cutaneous and is very fast acting and short lived in effect. For PD, it can be kept on hand in case of episodes of freeze, which it can relieve within minutes.
Dopamine agonists often induce nausea, and, ironically, are often prescribed along with domperidone, a D2 receptor antagonist which blockades the D2 receptors in the body. However, since it cannot cross the blood-brain barrier, it doesn't affect the action of dopamine agonist drugs on the brain.
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In a forthcoming article, we will consider the practical ramifications of the reality of dopamine cell receptor upregulation and downregulation for people with PD.