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TAAR – THE NEW RECEPTOR ON THE BLOCK

“What is now proved was once only imagined.” — William Blake

**This is a rather complicated post intended for those who have background or special interest in neurochemistry and/or psychopharmacology.

Trace amines are biologically related to major amines such as norepinephrine and dopamine but they are present in much smaller concentrations. Trace amines molecules include phenythylamine (PEA), tyramine, octopamine, tryptamine, 3-iodothyronamine (T1AM) and a number of others.

Trace amine-associated receptor 1 (TAAR1) is a G-coupled protein receptor that was discovered in 2001, and since then at least eight more species of this receptor type have been identified in various tissues (stomach, small intestine, liver, kidneys, lymphocytes, astrocytes, monoaminergic neurons). In the past few years, there has been a rapidly emerging understanding about the important the role trace amines in the regulation of nervous system, metabolism and olfaction (sense of smell).

Before TAAR1 was identified, trace amines were  thought to have little biological function but in recent years, their role as very powerful neuromodulators has emerged. Via their action on TAAR receptors trace amines act as “master ” that essentially influence all other aminergic neurotransmitters (NE, DA, SE) in the central nervous system.  TAAR receptors also appear to be involved in the neuromodulation of glutamate, histamine, and GABA.

Their most profound influence appears to be on the release of catecholamines (norepinephrine and dopamine). TAAR1 is widely expressed in the primary monoaminergic areas of the brain and well positioned to modulate locomotor, emotional, and motivated behaviors that are traditionally associated with monoaminergic activity.

Trace amines are also believed to inhibit transporters of these molecules (NET transporter deficiency has been observed in some POTS patients). They can also affect a marked effect on the release histamine, which is another common problem in many patients. TAAR receptors are also involved in the neuromodulation of glutamate, GABA and serotonin.

TAAR receptors have been found in leukocytes and B lymphocytes, and are thought to be directly involved in regulation of immunity. This would explain the underlying immune system abnormalities found in CFS/POTS patients.

TAAR1 and TAAR 2 receptors are present in large numbers in  play a crucial role in olfaction (smell), in particular detection of volatile amines, which would explain the hallmark sensitivity to chemical smells, present to some degree in all dysautonomic illness but in particular in MCS.

Trace amines molecules act as indirect sympathomimetic agents involved in regulation of sympathetic system. They also have been shown to have a direct effect on alpha1 and alpha2 receptors. It is possible, that the over-activation of sympathetic nervous system combined with the catecholamine depletion due to the persistent release (a phenomenon known as “tachyphylaxis” is what causes the infamous “tired but wired” state, when it feels like nerve cells are pushing on the gas pedal while running on an empty gasoline tank.

 Trace amines synthesis appears to be closely related to the metabolism of thyroid hormones, and due to its synthesis within intestinal lumen, also possibly to gut flora. (Hartmut et al, 2017).

High levels of 3-iodothyronamine (T1AM) have been shown to induce a state of “torpor/immobility” in rodents. This would correlated with a physiological signature of “dauer’ described by R. Naviaux (Naviaux et al, 2016) et al in their recent CFS metabolomics study. It appears that T1AM plays a pivotal role in orchestrating neuronal energy balance in conjunction with thyroid hormone. ( from my former ME/CFS patient standpoint “torpor” is actually a very apt description of what I’ve experienced).

Overstimulation of TAAR receptors has been linked to the oxidative damage to neurons and a decrease in glutamate clearance (Cisneros IE, Ghorpade A, 2014).

There is some evidence that TAAR receptors may play a role in regulation of ACTH, and as we all know hypothalamic dysregulation of cortisol levels is common in patients with CFS, POTS and fibromyalgia. (Zucci et al, 2006)

TAAR receptors regulate cellular cAMP accumulation via their effect on adenylyl cyclase. The rank order of potency for cAMP production is

p-tyramine> β-phenylethylamine>tryptamine>octopamine>m-tyramine>>dopamine (Zucci et al, 2006).

 Recent study identified TAAR1 gene SNPs as one of several abnormal genes in fibromyalgia patients cohort. Trace amines and TAAR receptors have been shown to be involved in regulation of nociceptive (pain) pathways and locomotion in spinal cord neuronal pathways (Smith SB et al 2012).

REFERENCES:

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21. Hartmut H. Glossmann1 and Oliver M. D. Lutz2 Torpor: The Rise and Fall of

3-Monoiodothyronamine from Brain to Gut—From Gut to Brain?. Frontiers in Endocrinology. Review published: 31 May 2017. doi: 10.3389/fendo.2017.00118

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