Trace Amines and Their Receptors.

Trace amines are endogenous compounds classically regarded as comprising β-phenylethyalmine, p-tyramine, tryptamine, p-octopamine, and some of their metabolites. They are also abundant in common foodstuffs and can be produced and degraded by the constitutive microbiota. The ability to use trace amines has arisen at least twice during evolution, with distinct receptor families present in invertebrates and vertebrates. The term "trace amine" was coined to reflect the low tissue levels in mammals; however, invertebrates have relatively high levels where they function like mammalian adrenergic systems, involved in "fight-or-flight" responses. Vertebrates express a family of receptors termed trace amine-associated receptors (TAARs). Humans possess six functional isoforms (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9), whereas some fish species express over 100. With the exception of TAAR1, TAARs are expressed in olfactory epithelium neurons, where they detect diverse ethological signals including predators, spoiled food, migratory cues, and pheromones. Outside the olfactory system, TAAR1 is the most thoroughly studied and has both central and peripheral roles. In the brain, TAAR1 acts as a rheostat of dopaminergic, glutamatergic, and serotonergic neurotransmission and has been identified as a novel therapeutic target for schizophrenia, depression, and addiction. In the periphery, TAAR1 regulates nutrient-induced hormone secretion, suggesting its potential as a novel therapeutic target for diabetes and obesity. TAAR1 may also regulate immune responses by regulating leukocyte differentiation and activation. This article provides a comprehensive review of the current state of knowledge of the evolution, physiologic functions, pharmacology, molecular mechanisms, and therapeutic potential of trace amines and their receptors in vertebrates and invertebrates.