Trace amines: Identification of a family of mammalian G protein-coupled receptors

Abstract

Tyramine, ␤-phenylethylamine, tryptamine, and octopamine are biogenic amines present in trace levels in mammalian nervous systems. Although some ''trace amines'' have clearly defined roles as neurotransmitters in invertebrates, the extent to which they function as true neurotransmitters in vertebrates has remained speculative. Using a degenerate PCR approach, we have identified 15 G protein-coupled receptors (GPCR) from human and rodent tissues. Together with the orphan receptor PNR, these receptors form a subfamily of rhodopsin GPCRs distinct from, but related to the classical biogenic amine receptors. We have demonstrated that two of these receptors bind and͞or are activated by trace amines. The cloning of mammalian GPCRs for trace amines supports a role for trace amines as neurotransmitters in vertebrates. Three of the four human receptors from this family are present in the amygdala, possibly linking trace amine receptors to affective disorders. The identification of this family of receptors should rekindle the investigation of the roles of trace amines in mammalian nervous systems and may potentially lead to the development of novel therapeutics for a variety of indications.

Are Caenorhabditis elegans receptors useful targets for drug discovery: Pharmacological comparison of tyramine receptors with high identity from C. elegans (TYRA-2) and Brugia malayi (Bm4)

“…For example, all Gα scoupled receptors cluster in clade I and we predict that MsOA, AgOA and CbP03135 are also Gα s -coupled OA receptors. As predicted HsTAAR1, that has high affinity to TA and couples to Gα s , is found in clade I supporting clustering based on coupling and not ligandspecificity [29]. In contrast, all Gα i/o characterized receptors fall into clade II and we predict that AsTA/OA, CbP1888, AgTA2, PxTA, BmiOA, LsOA2, Bm4, CbP02670 are Gα i/ocoupled TA receptors.…”

“…The G-protein coupling of 18 of the 34 receptors is known or strongly suggested through experimentation [18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]. An unrooted phylogenetic tree of annotated TA/OA receptors using maximal parsimony was compiled using PAUP (Figure 2).…”

Ethological analyses of crayfish behavior: a new invertebrate system for measuring the rewarding properties of psychostimulants

“…For instance, the trace amine tyramine (TA) appears to play an integral role in the development of behavioral sensitization to cocaine [38] such that circadian gene regulation, TA biosynthesis and behavioral sensitization are tightly coupled in fruit flies [2]. Interestingly, subsequent work in mammals demonstrated the importance of circadian rhythmicity for psychostimulant sensitization [1,44] and, furthermore, identified a population of high-affinity TA receptors in the ventral tegmental area [11], a focal region of DA-rich cell bodies thought to be a primary component of reward circuitry in the mammalian brain. Although trace amines like TA have historically received less experimental attention than other monoamines, there exists a large literature documenting their relationship to disturbances in affect and cognition (see ref.…”

Characterization of a tyramine receptor from Caenorhabditis elegans

“…Studies on the physiological role and signaling of OA and its precursor TA have focused largely on insects where, OA and TA regulate a variety of processes, including energy generation via fat body metabolism (Downer 1979;Wang et al 1990;Blau and Wegener 1994;Park and Keeley 1998), regulation of egg-laying (Monastirioti et al 1996;Torfs et al 2000) and induction of feeding (Braun and Bicker 1992). The role of TA and OA in mammals is not well studied but has recently gained much attention due to the isolation of human and rodent receptors that specifically bind TA and couple to G as , highlighting the need to re-evaluate the role of these trace amines in vertebrates (Borowsky et al 2001).In the free-living nematode, Caenorhabditits elegans, a putative tyramine-b hydroxylase (tbh-1) has been identified and localized to the two RIC interneurons, suggesting they are octopaminergic (Alkema and Horvitz, personal communication). Mutants lacking tbh-1 move more slowly than wild type, indicating a role for OA in locomotion.…”