Differential Modulation of Beta-Adrenergic Receptor Signaling by Trace Amine-Associated Receptor 1 Agonists

Trace amine-associated receptors (TAAR) are rhodopsin-like G-protein-coupled receptors (GPCR). TAAR are involved in modulation of neuronal, cardiac and vascular functions and they are potentially linked with neurological disorders like schizophrenia and Parkinson's disease. Subtype TAAR1, the best characterized TAAR so far, is promiscuous for a wide set of ligands and is activated by trace amines tyramine (TYR), phenylethylamine (PEA), octopamine (OA), but also by thyronamines, dopamine, and psycho-active drugs. Unfortunately, effects of trace amines on signaling of the two homologous β-adrenergic receptors 1 (ADRB1) and 2 (ADRB2) have not been clarified yet in detail. We, therefore, tested TAAR1 agonists TYR, PEA and OA regarding their effects on ADRB1/2 signaling by co-stimulation studies. Surprisingly, trace amines TYR and PEA are partial allosteric antagonists at ADRB1/2, whereas OA is a partial orthosteric ADRB2-antagonist and ADRB1-agonist. To specify molecular reasons for TAAR1 ligand promiscuity and for observed differences in signaling effects on particular aminergic receptors we compared TAAR, tyramine (TAR) octopamine (OAR), ADRB1/2 and dopamine receptors at the structural level. We found especially for TAAR1 that the remarkable ligand promiscuity is likely based on high amino acid similarity in the ligand-binding region compared with further aminergic receptors. On the other hand few TAAR specific properties in the ligand-binding site might determine differences in ligand-induced effects compared to ADRB1/2. Taken together, this study points to molecular details of TAAR1-ligand promiscuity and identified specific trace amines as allosteric or orthosteric ligands of particular β-adrenergic receptor subtypes

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

Cardiac effects of thyronamines

3-Iodothyronamine (T(1)AM) is an endogenous compound derived from thyroid hormone through decarboxylation and deiodination, which interacts with a novel G protein-coupled receptor, known as trace amine-associated receptor 1 (TAAR1). TAAR1 and other receptors of this family are expressed in several tissues, including the heart. Functional effects have been observed after administration of exogenous T(1)AM: in the isolated heart, a negative inotropic and chronotropic action was produced, and the resistance to ischemic injury was increased, possibly as a consequence of an action on intracellular calcium homeostasis. Extracardiac effects include reduction of body temperature, increased lipid versus carbohydrate metabolism, and modulation of insulin secretion. T(1)AM might play an important physiological or pathophysiological role, and this signaling system might allow the development of new therapeutical agents

Metabolic effects of 3-iodothyronamine in hepatocytes

3-iodothyronamine (T1AM) is an endogenous thyroid hormone derivative which produces profound metabolic effects such as a shift in fuel substrate utilization from carbohydrates to lipid. Thus, in the present work we investigated the effects of T1AM on hepatic glucose metabolism. To assess metabolite release, human hepatocellular carcinoma cells (HepG2) were exposed for 4 h to different concentrations of exogenous T1AM (0.1, 1 and 10 μM) in glucose production buffer (DME base containing pyruvate and lactate). Cell culture medium was then collected and glucose and ketone body (acetoacetate and β-hydroxybutyrate) levels were evaluated. In addition, isolated rat liver preparations were perfused either with Krebs-Henseleit buffer or glucose production buffer containing 1 μM T1AM. The effluent perfusate was then collected for 60 min at 5 min intervals to measure the release of glucose and ketone bodies (acetoacetate and β-hydroxybutyrate). In HepG2, only infusion with 1 μM T1AM induced a significant increase in glucose production (9.11±0.37 vs 7.48±0.14 μg/mg of total proteins in cell lysate, P<0.01), and a significant decrease in acetoacetate release (252.4±10.5 vs 286.8±7.2 nmol/ mg of total proteins in cell lysate P<0.05). Liver perfusion with glucose production buffer in the presence of 1 μM T1AM also showed a significant increase of glucose production (0.555±0.062 vs 0.369±0.043 mg/min per g P<0.05), while infusion with Krebs-Henseleit buffer did not produce any significant change in glucose metabolism. In conclusions our preliminary data suggested that T1AM stimulated gluconeogenesis and inhibited ketogenesis under conditions of glucose deprivation. Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project