Caracterización farmacológica y funcional de los receptores nicotínicos de las células cromafines de la médula adrenal de la rataplasticidad inducida por un modelo de estrés crónico

Resumo

Chromaffin cells from the adrenal medulla are well known for their contribution to the classical "fly or fight" stress response through the release of catecholamines into blood circulation. Nicotinic acetylcholine receptors (nAChRs) at the chromaffin cell plasma membrane are the first molecular step in the so-called "excitation-secretion coupling" process, which translates the release of acetylcholine from splanchnic nerve terminals into the exocytosis of catecholamines. Neuronal nAChRs are ligand-gated ion channels with pentameric structure formed by multiple combinations of different α (α2-α10) and β (β3-β4) subunits. The "ganglionic" type (α3β4* or α3β2*) of nAChR has long been considered the predominant nAChR expressed by chromaffin cells. Notwithstanding, results from several researchers concur in that it is responsible for not more than 50% of the celĺs nicotinic current (Yokotani y col., 2002; Di Angelantonio y col., 2003; Pérez-Alvarez y col., 2102). In this context, the finding of a new type of nAChRs formed α9 and/or α10 subunits in the hair cells of the cochlea, prompted the search and ultimately led to their identification in chromaffin cells from the rat adrenal gland (Solís, 2006; Colomer y col., 2010). Moreover, the observation that nAChRs α9* expression augments in chromaffin cells from animals exposed to a chronic stress together with their biophysical -high Ca2+ permeability- and pharmacological properties -activation by muscarinic agonists, like oxotremorine-M, and block by nicotine- confer this signaling molecule unique capabilities among nAChRs to inhibit cell's electrical activity and points to it as a potential drug target allowing a selective pharmacological intervention in a variety of stress-related disorders. Both circumstances, incomplete characterization of nAChRs from chromaffin cells and stress-induced plasticity of nAChRs drove the present PhD thesis work. The main objective has therefore been the pharmacological characterisation of nAChRs in rat chromaffin cells and the study of their modification in an experimental model of chronic systemic cold (4ð C over 5 days) ...