Tyrosine phosphorylation differentially fine-tunes ionotropic and metabotropic responses of human alpha 7 nicotinic acetylcholine receptor

摘要

The alpha 7 nicotinic acetylcholine receptor is involved in neurological, neurodegenerative, and inflammatory disorders. It operates both as a ligand-gated cationic channel and as a metabotropic receptor in neuronal and non-neuronal cells. As protein phosphorylation is an important cell function regulatory mechanism, deciphering how tyrosine phosphorylation modulates alpha 7 dual ionotropic/metabotropic molecular function is required for understanding its integral role in physiological and pathological processes. alpha 7 single-channel activity elicited by ACh appears as brief isolated openings and less often as episodes of few openings in quick succession. The reduction of phosphorylation by tyrosine kinase inhibition increases the duration and frequency of activation episodes, whereas the inhibition of phosphatases has the opposite effect. Removal of two tyrosine residues at the alpha 7 intracellular domain recapitulates the effects mediated by tyrosine kinase inhibition. The tyrosine-free mutant receptor shows longer duration-activation episodes, reduced desensitization rate and significantly faster recovery from desensitization, indicating that phosphorylation decreases alpha 7 channel activity by favoring the desensitized state. However, the mutant receptor is incapable of triggering ERK1/2 phosphorylation in response to the alpha 7-agonist. Thus, while tyrosine phosphorylation is absolutely required for alpha 7-triggered ERK pathway, it negatively modulates alpha 7 ionotropic activity. Overall, phosphorylation/dephosphorylation events fine-tune the integrated cell response mediated by alpha 7 activation, thus having a broad impact on alpha 7 cholinergic signaling.