OBJECTIVES

One of the most important concepts that were coined at the dawn of pharmacological studies is the concept of RECEPTOR. Early pharmacologists realized that small amounts of certain substances had profound effects on physiological systems and small changes in the chemical composition of these substances could take to profound differences in their activity. All this led to the notion that something in biological systems should be responsible for decoding the chemical information contained in these substances and translating it into a physiological effect. This something was called the RECEPTOR of that substance.

Today, molecular biology has made a fundamental contribution to pharmacology and it was recognized that the targets of drugs used for therapeutic purposes can range from proteins present in the cell membrane or cytoplasm to enzymes, ion channels, transporters, or DNA.

MEMBERS

FEDERICO MONCZOR

Independent Researcher (CONICET).

VALERIA TORRALBA

PhD candidate (ANPCyT).

C. DANIEL ZAPPIA

Assistant proffesor (Medicinal Chemistry, UBA).

LINES OF RESEARCH

CROSSTALK BETWEEN GLUCOCORTICOID AND HISTAMINERGIC RECEPTORS. THERAPEUTIC IMPLICATIONS.

The main objective of the present line is to study how the ligands of receptors coupled to G proteins (GPCRs) can modulate the activation of the glucocorticoid receptor (GR). Our working group focuses on the study of processes mediated by histamine, a biogenic amine with numerous functions, whose receptors belong to the superfamily of GPCRs. On the other hand, the genomic effects of glucocorticoids are exerted through the interaction with an intracellular receptor that functions as a transcription factor per se, or as a regulator of several transcription factors. Its deregulation leads to innumerable pathologies and, in fact, of the totality of commercialized drugs, 27% acts on the first group of receptors and 13% on the second.

The study carried out is relevant considering that antihistamine drugs that act by antagonizing the effects of histamine on the H1 and H2 receptors are prescribed jointly with certain corticosteroids for the treatment of several disorders. Moreover, there are commercial formulations that present the association of these two types of drugs.

So far we have shown that the ligands of the histaminergic system are capable of potentiating the action of glucocorticoids and we are bound to discern the therapeutic potential of this association in models of murine asthma.

MODULATION OF GLUCOCORTICOID SYSTEM ACTIVITY BY THE CANABINOID SYSTEM RECEPTORS

Glucocorticoids belong to the family of steroid hormones and are involved in the regulation of a wide variety of biological functions. Its synthesis and release by the adrenal medulla is regulated by the hypothalamic-pituitary-adrenal axis in response to different stimuli, including stress. Among others, they exert numerous effects on the central nervous system (CNS), mainly related to the establishment of working memory and long-term experiences with a high emotional component. The glucocorticoids exert their effects by acting on an intracellular receptor (GR), whose activity is classically associated with its genomic effects acting as a transcription factor per se, or as a regulator of various transcription factors. There is evidence pointing to the endocannabinoid system (SEC) as a candidate that participates in the regulation of the processes mediated by glucocorticoids in the CNS. The endocannabinoid ligands exert their effects through two receptors (CB1 and CB2), both belonging to the superfamily of receptors coupled to heterotrimeric G proteins (GPCRs). For its part, the SEC modulates a number of physiological processes and is essential in the adaptive response to stress, being also related to the consolidation processes of memory and learning. However, the effect of SEC signaling on the glucocorticoid system at the CNS level has not been studied.

In this context, our general objective is to study the regulation of the glucocorticoid system activity by the ligands of the endocannabinoid system and to delve into the molecular mechanisms of interaction between both systems.

The proposed study is relevant considering that the receptors of both systems are co-expressed in diverse structures of the CNS, especially in the hippocampus and in the cerebral amygdala; that both systems are involved in memory and learning processes; and that it has been suggested that the SEC is a necessary and essential participant for the effects of glucocorticoids in the regulation of the memory of post-traumatic experiences with a high emotional component.

IMPORTANCE OF THE COMPONENTS’ STOICHIOMETRY OF TRANSDUCTION SIGNALING PATHWAYS ON LIGANDS’ ACTION EXERCISING THEIR EFFECT ON GPCRS

In general, extracellular signal transduction occurs through different types of membrane receptors, among which is the superfamily of G-protein coupled receptors (GPCRs). Our working group focuses on the study of processes mediated by histamine. This compound is a biogenic amine with numerous functions, whose deregulation leads to various pathologies. Results from our laboratory show that, both in a conformation induced by certain ligands, and spontaneously, the histamine H1 and H2 receptors are able to acquire an inactive but coupled to the G protein conformation, interfering in this way in the signaling of other GPCRs, through a molecular sequestration effect. In this context, we intend to study the effect of the variation in the amounts of the various proteins involved on the signaling of the GPCRs, and to study if the effect of molecular sequestration observed is a particularity of the receptors to histamine and its ligands or it is a more general phenomenon. Our approach involves the development of theoretical models that help predict the behavior of receptors for a better understanding of their activity in order to intervene on them for therapeutic purposes. The knowledge generated in this field is important for the understanding of biological systems in terms of their response to ligands of GPCRs and provides new basis for the rational use of histaminergic ligands.

OUTSTANDING PUBLICATIONS OF THE LAST YEARS

  1. A Model of Glucocorticoid Receptor Interaction With Coregulators Predicts Transcriptional Regulation of Target Genes. Monczor F, Chatzopoulou A, Zappia CD, Houtman R, Meijer OC, Fitzsimons CP. Front Pharmacol. 2019 Mar 13;10:214. doi: 10.3389/fphar.2019.00214. eCollection 2019.
  2. Effect of mutation of Phe 2436.44 of the histamine H2 receptor on cimetidine and ranitidine mechanism of action. Granja-Galeano G, Zappia CD, Fabián L, Davio C, Shayo C, Fernández N, Monczor F. Biochem Pharmacol. 2017 Dec 15;146:117-126. doi: 10.1016/j.bcp.2017.09.014.
  3. Histamine H2Receptor in Blood Cells: A Suitable Target for the Treatment of Acute Myeloid Leukemia. Monczor F, Copsel S, Fernandez N, Davio C, Shayo C. Handb Exp Pharmacol. 2017;241:141-160. doi: 10.1007/164_2016_8. Review.
  4. Current knowledge and perspectives on Histamine H1 and H2 receptor pharmacology: Functional selectivity, receptor crosstalk, and repositioning of of classic histaminergic ligands. Monczor F and Fernandez N. Mol Pharmacol. 2016 Nov 90(5):640-648. doi: 10.1124/mol.116.105981. Review.
  5. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. Zappia CD, Granja-Galeano G, Fernández N, Shayo C, Davio C, Fitzsimons CP, Monczor F. Sci Rep. 2015 Dec 4;5:17476. doi: 10.1038/srep17476.
  6. Antihistaminergics and inverse agonism: potential therapeutic applications. Monczor F, Fernandez N, Fitzsimons CP, Shayo C, Davio C. Eur J Pharmacol. 2013 Sep 5;715(1-3):26-32. doi: 10.1016/j.ejphar.2013.06.027. Epub 2013 Jul 4. Review.
  7. Measurement of inverse agonism in β-adrenoceptors. Taira CA, Monczor F, Höcht C. Methods Enzymol. 2010;485:37-60. doi: 10.1016/B978-0-12-381296-4.00003-8.
  8. Expression of a G protein-coupled receptor (GPCR) leads to attenuation of signaling by other GPCRs: experimental evidence for a spontaneous GPCR constitutive inactive form. Tubio MR, Fernandez N, Fitzsimons CP, Copsel S, Santiago S, Shayo C, Davio C, Monczor F. J Biol Chem. 2010 May 14;285(20):14990-8. doi: 10.1074/jbc.M109.099689. Epub 2010 Mar 18.

ONGOING FUNDING

  • Scientific and Technological Promotion Agency – PICT-2016-2612 Project. «Cross-talk between glucocorticoid and histaminergic receptors. Potential therapeutic implications”. Amount: $ 850500.
  • National Council for Scientific and Technical Research -CONICET 2015-17- PIP 0562. «Molecular mechanisms of cross-talk between histamine H1 and H2 receptors». Amount: $ 330000.

COLLABORATIONS

Internationals

Dr. CP Fitzsimons. Faculteit der Natuurwetenschappen, Wiskunde en Informatica. Swammerdam Institute for Life Sciences. UVA. Amsterdam. The Netherlands.

Dr. Onno Meijer. Faculty of Science, Leiden/Amsterdam Center for Drug Research, Medical Pharmacology. The Netherlands.

Nationals

Dra. Ana Franchi. Centro de Estudios Farmacológicos y Botánicos – CEFyBo-CONICET-UBA.

Dra. Alejandra Goldman. Laboratorio de Inmunología, Vacunas y Alergia. Centro de Estudios en Salud y Medioambiente. CESyMA. Universidad Nacional de San Martín.

Dra. Adalí Pecci. Instituto de Fisología, Biología Molecular y Neurociencias – IFiByNe-CONICET-UBA.