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Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation In Graduate Physical and Life Sciences PhD Pharmacology Abstract ID# 1081 Is TAAR1 a Potential Therapeutic Target for Immune Dysregulation in Drug Abuse? Fleischer, Lisa M; Tamashunas, Nina and Miller, Gregory M Addiction Sciences Laboratory, Northeastern University, Boston MA 02115 Abstract Discovered in 2001, Trace Amine Associated Receptor 1 (TAAR1) is a direct target of Data and Results amphetamine, methamphetamine and MDMA. It is expressed in the brain reward circuity and modulates dopamine transporter function and dopamine neuron firing rates. Newly-developed compounds that specifically target TAAR1 have recently been investigated in animal models In addition to brain, TAAR1 is expressed in immune cells METH promotes PKA and PKC Phosphorylation through TAAR1 as candidate therapeutics for methamphetamine, cocaine and alcohol abuse. These studies • We treated HEK/TAAR1 cells and HEK293 involving classic behavioral measures of drug response, as well as drug self-administration, Rhesus and Human cells with vehicle or METH, with and without strongly implicate TAAR1 as a potential therapeutic target for the treatment of addiction. In activators and inhibitors of PKA and PKC. addition to its central actions, we demonstrated that TAAR1 is upregulated in peripheral blood Cells Lines mononuclear cells (PBMC) and B cells following immune activation, and that subsequent • We performed Western blotting experiments to activation of TAAR1 by methamphetamine stimulates cAMP, similar to the function of measure levels of phospho-PKA and phospho- adenosine A2 receptors which are also present in immune cells and play a critical role in the PKC. immune response. Here, we are investigating the relationship between TAAR1 and the • We found that specific activators of PKA and adenosine A2 receptor at the level of cellular signaling and receptor dimerization. We PKC promote upregulation of phosphor-PKA hypothesize that both receptors synergistically elevate cAMP through their Gs coupling, and and phosphor-PKC, respectively, in both that specific TAAR1 drugs may have immunomodulatory effects through this shared signaling HEK/TAAR1 cells and HEK293 cells. mechanism. This hypothesis is supported by the observation that methamphetamine is a • However, METH promoted upregulation of potent TAAR1 agonist that has profound effects on immune system function. Accordingly, phospho-PKA and phospho-PKC only in deciphering the role of TAAR1 in methamphetamine action and immune regulation may lead HEK/TAAR1 cells. to the development of novel addiction therapeutics that combat both central addictive mechanisms, as well as immunological aberrations that occur in drug abuse. • Antibodies: Phospho-PKA (Abcam ab5815); Phospho-PKC (Abcam ab23513); TAAR1 (Imgenex IMG-71855) Antibodies: Introduction Phospho-PKA (Abcam ab5815); Drugs: TAAR1 has a wide agonist spectrum Phospho-PKC (Abcam Methamphetamine (1mM); PKA Inhibitor: H89 (10 mM); • Trace-Amine Associated Receptor 1 (TAAR1) is a Gs-linked GPCR first cloned in 2001. METH is a potent TAAR1 agonist ab23513); PKC Inhibitor: Ro32-0432 (10 mM); PKA activator: • TAAR1 is a target for trace amines, common biogenic amines, thyronamines, TAAR1 (Imgenex IMG-71855) 8-Br-cAMP (100 mM) PKC activator: b-PMA (1 mM) amphetamine, methamphetamine (METH), and MDMA. • TAAR1 is expressed in some dopamine neurons, and has been shown to modulate TAAR1 is upregulated in activated immune cells, and DAT function, D2 function, and DA neuronal firing rates. • Newly-developed specific TAAR1-targeted agonists are being tested as therapeutics for METH promotes PKA and PKC phosphorylation only in the psychiatric and addiction disorders. presence of TAAR1 • In addition to brain, TAAR1 is expressed in immune cells. Aims and Methods We hypothesize that TAAR1 is an immunomodulator. We speculate that TAAR1 signaling may be synergistic with Adenosine A2A receptor signaling. A2A is also Gs-linked and plays • We used a CRE-Luciferase assay to perform a dose-response study using a prominent role in orchestrating the immune response. Further, we speculate that TAAR1 common biogenic amines, trace amines and amphetamine-like mediates some of the immunological actions of methamphetamine, and may serve as a therapeutic target. psychostimulants. Data is generated in TAAR1-transfected HEK293 cells. The preliminary data shown here suggests that immunological actions of METH may be The TAAR1 agonist METH selectively activates NFAT (Ca++/PKC) mediated through TAAR1. Moving forward, we will explore whether TAAR1 signaling is interactive with A2A signaling, and whether TAAR1 and A2A form heteromers. and CREB (cAMP/PKA) pathways 1) Characterize human cell lines for TAAR1 and A2A co-expression by developing sensitive and specific PCR probes for TAAR1 and for A2A detection in: -PM1 cells (human CD4+ T-lymphoid cells) Vehicle in HEK293 cells -SH-S5Y5 cells (human neuroblastoma, bone marrow cells) 2) Assess cellular signaling pathways utilized by TAAR1 and A2A using Cignal45 TAAR1 expression upregulation following immune activation and TAAR1- assays and Lenti-reporter cell lines to assess TAAR1 and A2A signaling. METH in HEK293 cells dependent phosphorylation of PKA and PKC by METH in rhesus monkey 3) Determine whether TAAR1 and A2A form heteromers in vitro using YFP- and Luc- PBMC. tagged TAAR1 and A2A constructs and assessing BRET in transfected cells that natively METH in HEK/TAAR1 cells a) TAAR1 expression was upregulated in PBMC by stimulation with PHA (1 express TAAR1 and A2. μg/ml for 48 h) and is compared to TAAR1/HEK293 cells. b) Phosphorylation status of PKA and PKC in untreated PBMC and following Conclusions vehicle, EPPTB (10 μM), methamphetamine (1 μM), and EPPTB plus METH Preliminary findings indicate that: treatments assessed by Western blot using anti-phospho-PKA and anti- • TAAR1 is expressed in a variety of immune cell types. phospho-PKC antibodies. • METH is an agonist at TAAR1. c) Quantification and comparison of PKA and PKC phosphorylation in PHA- • TAAR1 activates both the cAMP/PKA and the Ca++/PKC pathways. • We used a Cignal45 array assay (SABiosciences) to determine whether additional treated PBMC was done by densitometry using IMAGEJ software. **: p<0.0001 • TAAR1 is upregulated in activated immune cells, and METH stimulation of both the signaling pathways are stimulated by TAAR1 activation. for indicated comparisons. ++ cAMP/PKA and the Ca /PKC pathways is TAAR1-dependent. • Consistently, we found that NFAT (Ca++/PKC) and CREB (cAMP/PKA) pathways Our future studies will explore whether TAAR1 signaling is interactive with A2A signaling were activated by METH in a TAAR1-dependent manner. Support and References NIDA 025697 (GM), 022323 (GM), DA030177 (GM). and whether TAAR1 and A2A form heteromers. Some data shown is published in: Panas et al, J Neuroimmune Pharmacol (2012) 7:866–876..
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