Trace Amine-Associated Receptors as Novel Therapeutic Targets for Immunomodulatory Disorders

Abstract

Trace amines and their receptors (trace amine-associated receptors; TAARs) are an emerging pharmacological target for the treatment of human disorders. While most studies have focused on their therapeutic potential for neurologic and psychiatric disorders, TAARs are also expressed throughout the periphery, including prominent expression in human leukocytes. Furthermore, recent independent, unbiased metabolomic studies have consistently identified one or more TAAR ligands as potential etiologic factors in inflammatory bowel disease (IBD). The putative role of TAARs in diseases such as IBD that are associated with hyperactive immune responses has not, however, previously been systematically addressed. Here, we review the current state of the knowledge of the effects of TAARs on leukocyte function, in particular in the context of mucosal epithelial cells that interface with the environment; developing a model whereby TAARs may be considered as a novel therapeutic target for disorders associated with dysregulated immune responses to environmental factors. In this model, we hypothesize that altered trace amine homeostasis results in hyperactivity of the immune system. Such loss of homeostasis can occur through many different mechanisms including TAAR polymorphisms and altered trace amine load due to changes in host synthesis and/or degradative enzymes, diet, or microbial dysbiosis. The resulting alterations in TAAR functioning can then lead to a loss of homeostasis of leukocyte chemotaxis, differentiation, and activation, as well as an altered ability of members of the microbiota to adhere to and penetrate the epithelial cell layers. Such changes would generate a pro-inflammatory state at mucosal epithelial barrier layers that can manifest as clinical symptomatology such as that seen in IBD. These alterations may also have the potential to induce systemic effects, which could possibly contribute to immunomodulatory disorders in other systems, including neurological diseases.

The trace aminergic system: a gender-sensitive therapeutic target for IBS?

“…It is proposed that through the production of bioactive metabolites, such as biogenic amines, the gut microbiota may increase an individual's susceptibility to GI inflammation via modification of intestinal epithelial function and mucosal immune activity [46,235]. For example, several intestinal microbes synthesize various amino acid decarboxylases, which means that they have the capability to sequester amino acids, convert them into TA, and thereby alter the distribution of metabolites, such as calcium, 5-HT, trimethylamine N-oxide (TMAO) and immune cell mediators in the host, as part of the symbiotic relationship between the gut microbiome and host.…”

“…It is important to note, however, that TAAR signalling is additionally complicated by three factors. Firstly, genetic variations in the form of TAAR polymorphisms, as well as their clinical relevance, cannot be excluded [46], since function-altering polymorphisms of TAAR1 [209] and TAAR2 [27] have already been reported. Secondly, TAAR expression is often recorded in acute, in vitro models.…”

Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

“…Even though the biological functions of ecnomotopic csGPCRs have not been fully characterized, they seem to have the potential to serve as therapeutic tools [61,62,63,64,65,66]. The current knowledge about the ecnomotopic expression of smell and taste receptors and their suggested physiological and pathological functions has been recently and carefully reviewed [29,32,67].…”

The neuropsychiatric manifestations of COVID-19: Interactions with psychiatric illness and pharmacological treatment

“…trace amine associated receptor 1 (TAAR1). TAAR1 in turn modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity [ 101 ], therefore implicating TAAR1 not only in immune-inflammatory disorders [ 102 ], but in the control of monoamine-driven psychotic behaviours [ 103 ].…”