Rapid Upregulation of α7 Nicotinic Acetylcholine Receptors by Tyrosine Dephosphorylation

Abstract

α7 nicotinic acetylcholine receptors (nAChRs) modulate network activity in the CNS. Thus, functional regulation of α7 nAChRs could influence the flow of information through various brain nuclei. It is hypothesized here that these receptors are amenable to modulation by tyrosine phosphorylation. In both Xenopus oocytes and rat hippocampal interneurons, brief exposure to a broad-spectrum protein tyrosine kinase inhibitor, genistein, specifically and reversibly potentiated α7 nAChR-mediated responses, whereas a protein tyrosine phosphatase inhibitor, pervanadate, caused depression. Potentiation was associated with an increased expression of surface α7 subunits and was not accompanied by detectable changes in receptor open probability, implying that the increased function results from an increased number of α7 nAChRs. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor-mediated exocytosis was shown to be a plausible mechanism for the rapid delivery of additional α7 nAChRs to the plasma membrane. Direct phosphorylation/dephosphorylation of α7 subunits was unlikely because mutation of all three cytoplasmic tyrosine residues did not prevent the genistein-mediated facilitation. Overall, these data are consistent with the hypothesis that the number of functional cell surface α7 nAChRs is controlled indirectly via processes involving tyrosine phosphorylation.