Babusyte and Krautwurst, Cell Biol: Res Ther 2013, 2:2 http://dx.doi.org/10.4172/2324-9293.1000103 Cell Biology: Research & Therapy Short Communication a SciTechnol journal In two very recent papers using primary cells, the detection of Tracing Amines to their amines, especially 2-PEA, by Taar4 [29], TAAR1 and TAAR2 [30], was reported to occur at concentrations five to six orders of magnitude Receptors: A Synopsis in Light lower than the amine concentrations used previously for cell cultures. Zhang et al. used perforated patch-clamp current recordings from the of Recent Literature dendritic knobs of olfactory sensory neurons from isolated mouse 1 Agne Babusyte and Dietmar Krautwurst * main olfactory epithelium (Figure 1A) [29]. By this method they were able to characterize eg. Taar4-expressing olfactory sensory neurons to be broadly tuned and highly sensitive towards certain amines. For Abstract instance, the most potent amine 2-PEA induced currents in Taar4- Trace amine-associated receptors (TAAR) have been an elusive olfactory sensory neurons at concentrations ranging from 1x10-14 M species of G protein-coupled receptors (GPCR), so far, mainly to 3x10-9 M. In the work presented by Babusyte et al., the same amine because of their suboptimal expression in heterologous cell systems. Little connection could be established between the name- 2-PEA induced immune cell functions at concentrations ranging -11 -8 giving low physiological concentrations of their putative amine from 1x10 M to 1x10 M [30].When applied to neutrophils, T-cells agonists, and their tissue-specific biological function. At the same or B-cells, 2-PEA potently induced immune cell functions, such as time, there is growing evidence that suggests ectopic expression chemotactic migration, cytokine or immunoglobulin production, of certain TAAR, beyond their supposed typical tissue expression respectively (Figure 1B) [30]. Notably, TAAR1 and TAAR2 were as olfactory receptors in the olfactory epithelium, at least in mice. Two recent publications now shed light on the potent activation the receptors that mediated the 2-PEA-induced cellular responses by specific amines of certain TAAR in different primary cells: in in leukocytes. Both groups used gene-targeted approaches to olfactory sensory neurons (OSN) of the main olfactory epithelium (MOE) of mice, and, unexpectedly, in human peripheral blood leukocytes. Biogenic amines are bioactive compounds. They are derived from enzymatic de carboxylation of e.g. certain amino acids, and are metabolized by monoamine oxidases. Certain amines can be found in the plasma and in the central nervous system at low pico-to nanomolar concentra tions [1-6], and thus have been termed ‘trace amines’ [7,8]. Receptors, that specifically recog nise trace amines, initially have been found in the brain [7,9,10]. These ‘trace amine-associated receptors’ are members of rhodopsin-like Family A of GPCR. Recently, they have been identified in neurons of olfactory epithelia of mouse and zebrafish, where they may detect volatile amines as odorants or phero- mones [11-14]. Gene expression for 4 out of the six intact human TAAR genes was reported in human nasal mucosa at trace levels [15]. The impact of certain biogenicamines, such as β-phenylethylamine (2-PEA) and tyramine, on blood pressure, cardiac function, brain monoaminergic systems, and olfaction-guided behaviour has been demonstrated, mainly in studies with rodents [2,10,13,14,16-18]. Gene-targeted receptor knock-out mice revealed Taar1 as modulator of dopaminergic neurotransmission [19,20]. This animal model encouraged many laboratories to engage in a further characterization of e.g. human TAAR1 and its agonists in heterologous cell systems, such as HEK293, COS-7, CHO, and HGA16 cells, mainly using cAMP assays [7,9,21-27]. However, in these cell cultures expressing TAAR1, EC50 values (the concentration that yields 50% of maximum effect) for its gold standard agonist 2-PEA ranged from 0.1 µM to 1.9 µM, which is one to two orders of magnitude higher than the concentration of Figure 1: Ultrasensitive detection of amines by TAAR-expressing 2-PEA in plasma of healthy individuals [5,28]. primary cells. A) Amines, e.g. 2-PEA, potently activated Taar4 determined by means of patch-clamp current recordings from dendritic knobs of mouse *Corresponding author: Dietmar Krautwurst, German Research Center for OSN in isolated MOE, as reported by Zhang et al. [29]. B) Amines, e.g. 2-PEA, Food Chemistry – Leibniz Institute, Physiology, Freising, Germany, Tel: 08161- potently activated TAAR1- and TAAR2-dependent immune cell functions in 712634; Fax: 08161-712970; E-mail: [email protected] isolated human blood leukocytes, determined by chemotactic migration assay, and cytokine and immunoglobulin ELISA, as reported by Babusyte et al. [30]. Received: May 03, 2013 Accepted: June 27, 2013 Published: July 01, 2013 All articles published in Cell Biology: Research & Therapy are the property of SciTechnol, and is protected by copyright laws. International Publisher of Science, Copyright © 2013, SciTechnol, All Rights Reserved. Technology and Medicine Citation: Babusyte A, Krautwurst D (2013) Tracing Amines to their Receptors: A Synopsis in Light of Recent Literature. Cell Biol: Res Ther 2:3. doi:http://dx.doi.org/10.4172/2324-9293.1000103 demonstrate a receptor-dependent activation of the primary cells immune cell functions. Notably, mouse Taar1 and Taar2 were also investigated. detected in B-cells and NK-cells, but Taar1/TAAR1 is absent from the main olfactory epithelium (Figure 2). Whether a tissue expression of TAAR genes in general is considered ‘typical’ or ‘ectopic’ may, however, be merely a point of Taken together, the works published by Zhang et al. [29] and view, and depends on the data set available. For instance, expression Babusyte et al. [30] are important demonstrations of TAAR agonist- in the olfactory epithelium was shown for 14 of the 15 intact mouse mediated activities at physiological relevant amine concentrations, Taar genes [14], as well as for 4 of the 6 intact human TAAR genes suggesting that the major advantage of primary cells over cell [15]. Thus, and at least supported by experiments with Taar knock- cultures may be their sensitivity for agonists. The reason may be an out mice [31], TAAR are considered to typically function as olfactory optimal functional receptor expression, and the employment of the receptors. However, mouse Taar expression was also reported in the original receptor signal transduction cascade. On the other hand, gastrointestinal tract, spleen B-cells and NK-cells, spleen, and testis hard to obtain primary cells may be limited to investigation of rather [32-34]. Human TAAR expression was reported for the brain and small families of receptors, especially when considering the effort a variety of non-olfactory peripheral tissues (Figure 2) [7,34-39]. to establish large numbers of e.g. gene-targeted animals. Moreover, In different types of blood leukocytes, for instance, Babusyte et al. complexity due to co-expression of receptors may be a limiting factor recently now show expression of 5 out of the 6 intact human TAAR for any receptor deorphanization endeavor using primary cells. What [30]. Of these, TAAR1 and TAAR2 appear to be most abundantly are the amine concentrations that induce cellular functions in-vivo remains as an open question for the time being. These two recent expressed receptors in leukocytes. In contrast to mouse olfactory publications, nevertheless, encourage an optimistic view on the soon sensory neurons, TAAR1 and TAAR2 appear to dimerize in human identification of the specific agonists for TAAR, and other orphan leukocytes, where they play a major role in mediating amine-induced olfactory receptors. References 1. Galli E, Marchini M, Saba A, Berti S, Tonacchera M, et al. (2012) Detection of 3-iodothyronamine in human patients: a preliminary study. J Clin Endocrinol Metab 97: E69-74. 2. Berry MD (2004) Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem 90: 257-271. 3. D’Andrea G, Terrazzino S, Fortin D, Farruggio A, Rinaldi L, et al. 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