OBJECTIVES

The Signal Transduction and Drug Design Laboratory is oriented to the comprehension of those molecular mechanisms involved in the transmission of the biological information from extracellular to intracellular media in order to evoke a biologic response. The understanding of the regulatory mechanism underneath transduction process allows the identification of fundamental bases for rational drug design, and also the elucidation of the mechanisms of action of drugs.

Under these objectives and in collaboration with other groups, we carry out an interdisciplinary research involving in silico, in vitro and in vivo approaches to face the current drug design challenge.

MEMBERS

NATALIA C. FERNÁNDEZ

Investigadora Independiente CONICET, Profesora Adjunta Química Medicinal-FFyB-UBA.

EMILIANA ECHEVERRÍA

Becaria post-doctoral CONICET, Ayudante de segunda Química Biológica.

SONIA RIPOLL

Becaria doctoral CONICET.

MARTINA IRARRÁZAVAL

Becaria doctoral UBA.

RESEARCH LINES

GRK2 AS DRUG TARGET

GRK2 is involved in many diseases where GPCRs response regulation is altered. The main objective of this line relies on the identification and evaluation of compounds with inhibitory effect over RGS (Regulator of G protein Signaling) activity of GRK2. Hence, we consider GRK2 as a multidomain and multifunctional protein, with a desensitizing role beyond its kinase activity. In first instance, these studies will allow the validation of RGS activity of GRK2 as drug target, and the identification of potential inhibitors and the design of pharmacological prototypes for drug development.

GRK5 AS DRUG TARGET

GRK5 desensitizes beta-adrenergic receptors responsible for maintaining the contractility and functionality of the heart, and it has been shown to be overexpressed in patients and models with heart failure and hypertension. Also, the increased levels of GRK5 are associated with Alzheimer’s and Parkinson’s diseases. In this context, the objective of the present plan is to identify and evaluate compounds that inhibit GRK5 activity to obtain potential drugs for the treatment of chronic degenerative diseases.

BIASED AGONISM OF HISTAMINE RECEPTOR LIGANDS

Recently, it has been described that beyond second messenger modulation, many GPCRs can signal in a G-protein independent manner. Since historically the efficacy of histaminergic ligands was defined according to second messenger response, these findings gave rise to enquiries about actual ligands classification. The main objective of this research is to evaluate the faculty of histaminergic ligands (classically known as antagonists or inverse agonists) to promote desensitization and internalization of receptors, and to evoke other responses with G proteins not being involved. Identification y characterization of these events will allow the avoidance of undesired but specific effects.

PUBLICATIONS

  1. Novel inhibitors of phosphorylation independent activity of GRK2 modulate cAMP signaling. Echeverría E, Ripoll S, Fabián L, Shayo C, Monczor F, Fernández NC. Pharmacol Res Perspect. 2022 Apr;10(2):e00913. doi:10.1002/prp2.913.
  2. Biased agonism at histamine H1 receptor: Desensitization, internalization and MAPK activation triggered by antihistamines. Burghi V, Echeverría EB, Zappia CD, Díaz Nebreda A, Ripoll S, Gómez N, Shayo C, Davio CA, Monczor F, Fernández NC. Eur J Pharmacol. 2021 Apr 5; 896:173913. doi:10.1016/j.ejphar.2021.17391
  3. The Regulator of G Protein Signaling Homologous Domain of G Protein-Coupled Receptor Kinase 2 Mediates Short-Term Desensitization of β3-Adrenergic Receptor. Echeverría E, Cabrera M, Burghi V, Sosa M, Ripoll S, Yaneff A, Monczor F, Davio C, Shayo C, Fernández N. Front Pharmacol. 2020 Feb 21; 11:113. doi: 10.3389/fphar.2020.00113.
  4. Identification of inhibitors of the RGS homology domain of GRK2 by docking-based virtual screening. E Echeverría, AJ Velez Rueda, M Cabrera, E Juritz, V Burghi, L Fabián, C Davio, P Lorenzano Menna, N Fernández. Life Sci. 2019 239:116872.
  5. PI3K pathway is involved in ERK signaling cascade activation by histamine H2R agonist in HEK293T cells.N Alonso, A Diaz-Nebrada, F Monczor, JS Gutkind, C Davio, N Fernandez y C Shayo. Biophys Acta. 2016; 1860(9):1998-2007.
  6. Physiological implications of biased signaling at histamine H2 receptors.N Alonso, CD Zappia, M Cabrera, C Davio, C Shayo, F Monczor, N Fernández. Front Pharmacol. 2015. 6:45. doi:10.3389/fphar.2015.00045.
  7. G2/M cell cycle arrest and tumor selective apoptosis of malignant hematopoietic cells by a promising benzophenone thiosemicarbazone compound.Cabrera M, Gomez N, Remes Lenicov F, Echeverría E, Shayo C, Moglioni A, Fernández N, Davio C. PLoS ONE. 2015. 10(9):e0136878. Doi:10.1371/journal.pone.0136878.
  8. Effects of histamine H1 receptor signaling on glucocorticoid receptor activity. Role of canonical and non-canonical pathways. CD Zappia, G Granja-Galeano, N Fernández, C Shayo, C Davio, CP Fitzsimons y F Monczor. Sci Rep. 2015; 5:17476
  9. Dual role of cAMP in the transcriptional regulation of multidrug resistance-associated protein 4 (MRP4) in pancreatic adenocarcinoma cell lines.A Carozzo, F Diez, N Gomez, M Cabrera, C Shayo, C Davio, N Fernández. PLoS ONE. 2015. 10(3): e0120651. doi:10.1371/journal.pone.0120651.
  10. Signal transduction mechanism of biased ligands at histamine H2 receptors.Alonso N, Monczor F, Echeverria E, Davio C, Shayo C, Fernández N. Biochem J. 2014. 459(1):117-26.
  11. Antihistaminergics and inverse agonism. Potential therapeutic applications.Monczor F, Fernandez N, Fitzsimons CP, Shayo C, Davio C. Eur J Pharmacol.  (1-3)715:26-32.
  12. Oligodendrocyte Differentiation and Signaling After Transferrin Internalization: A Mechanism of Action.Pérez MJ, Fernandez N, Pasquini JM. Exp Neurol. 2013 248C:262-274.
  13. Cross-desensitization and cointernalization of H1 and H2 histamine receptors reveal new insights into histamine signal integration.Alonso N, Fernandez N, Notcovich C, Monczor F, Simaan M, Baldi A, Gutkind JS, Davio C, Shayo C. Mol Pharmacol. May;83(5):1087-98. 2013.
  14. Roles of phosphorylation dependent and independent mechanisms in the regulation of Histamine H2 receptor by G Protein-coupled Receptor Kinase 2.Fernandez N, Gottardo F, Alonso N, Monczor F, Shayo C, and Davio C. J Biol Chem. 286(33):28697-706. 2011.
  15. The expression of a G protein coupled receptor (GPCR) leads to the attenuation of other GPCRs signaling. Experimental evidence for a spontaneous GPCR constitutive inactive form.Tubio MR, Fernandez NC, Fitzsimons CP, Copsel S, Santiago SD, Shayo CC, Davio CA, Monczor F. J Biol Chem. 285:14990-8. 2010.

Book Chapters:

HISTAMINE RECEPTORS. Fernández N y Monczor F. En: Encyclopedia of Molecular Pharmacology, pp 1–6. Editores: Offermanns S y Rosenthal W. 2021. Springer International Publishing. ISBN: 978-3-030-21573-6.

HISTAMINE H2 RECEPTOR BIASED SIGNALLING METHODS para el volumen de Methods in Histamine Receptors de la colección SPRINGER PROTOCOLS. N Fernandez, C Shayo, C Davio, F Monczor. (Idioma: Inglés)

HISTAMINE H2 RECEPTOR IN BLOOD CELLS: A SUITABLE TARGET FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA del libro Handbook of Experimental Pharmacology. Editorial: Berlín, New York, Springer-Verlag, Alemania. ISSN 0171-2004. F Monczor, S Copsel, N Fernandez, C Davio, C Shayo. (Idioma: Inglés). Junio 2016.

EVALUACIÓN DE UN SISTEMA HORMONA-RECEPTOR del libro Fisiopatología Molecular y Clínica Endcorinológica. F Monczor, N Fernandez, JC Calvo. ISBN 978-987-45792-0-1. Neuhaus Industria Gráfica. Buenos Aires, Argentina 2015. RS Calandra, MB Barontini (Editores), MA Pisarev, GJ Juvenal, R Rey (Editores Asociados).

FUNDING

Subsidio para grupos en formación, Agencia de Promoción Científica y Tecnológica –SECYT, PICT 2015-2443. Identificación, obtención y evaluación de inhibidores de la actividad RGS de GRK2. IR. Dra. Natalia Fernández

Subsidio de la Universidad de Buenos Aires-UBACYT-20020130100624BA (2014-2017) - “Exclusión de AMPc y MRP4/ABCC4 como determinantes del balance AMPc-intracelular vs AMPc extracelular. Implicancias en la progreión celular maligna”. IR: Dr. Carlos Davio

Subsidio de la Agencia de Promoción Científica y Tecnológica. PICT-E-2014-0219 para la adquisición de equipamiento. IR: Dr. Carlos Davio.

Subsidio de la Agencia de Promoción Científica y Tecnológica, PICT-2013-2050 (2014-2017) “Exclusión de AMPc y MRP4/ABCC4 como determinantes del balance AMPc-intracelular vs AMPc extracelular. Implicancias en la progresión celular maligna”. Dr. Carlos Davio.

Subsidio del CONICET, PIP-112-201201-00562. 2013-2015. “Mecanimos de la regulación cruzada entre los receptores H1 y H2 a histamina”. IR: Dra. Carina Shayo.

COLLABORATIONS

Nationals

Javier A. Ramírez - Unidad de Microanálisis y Métodos Físicos en Química Orgánica (UMYMFOR).

Ernesto A. Aiello - Centro de Investigaciones Cardiovasculares Dr. Horacio E. Cingolani (CIC-CONICET-UNLP)

Verónica C. De Giusti - Centro de Investigaciones Cardiovasculares Dr. Horacio E. Cingolani (CIC-CONICET-UNLP)

Dr. Pablo Lorenzano-Menna - Investigador Adjunto CONICET de la Universidad Nacional de Quilmes.

Dra. Carina Shayo - Investigadora Independiente del CONICET del Instituto de Biología y Medicina Experimental (IBYME-CONICET).

Dr. Fernando Dominici - Investigador Independiente, CONICET, IQUIFIB-CONICET.

Dra. Andrea Randi - Investigadora Independiente, CONICET, Dpto de Bioquímica Humana, Facultad de Medicina, UBA.

Dr. Federico Remes Lenicov – Investigador Aistente CONICET, INBIRS-UBA-CONICET.