Regulation of the Neuronal Nicotinic Acetylcholine Receptor by Src Family Tyrosine Kinases

• Published in: The Journal of biological chemistry 2004-03, Vol.279 (10), p.8779-8786
• Main Authors: Wang, Kan, Hackett, John T., Cox, Michael E., van Hoek, Monique, Lindstrom, Jon M., Parsons, Sarah J.
• Format: Article
• Language: English
• Subjects: Cell Line; Chromaffin Cells - metabolism; Humans; Nerve Tissue - metabolism; Neurons - metabolism; Phosphorylation; Receptor Aggregation; Receptors, Nicotinic - metabolism; Signal Transduction; src Homology Domains; src-Family Kinases - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M309652200

Src family kinases (SFKs) are abundant in chromaffin cells that reside in the adrenal medulla and respond to cholinergic stimulation by secreting catecholamines. Our previous work indicated that SFKs regulate acetylcholine- or nicotine-induced secretion, but the site of modulatory action was unclear. Using whole cell recordings, we found that inhibition of SFK tyrosine kinase activity by PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo(3,4-d)pyrimidine) treatment or expression of a kinase-defective c-Src reduced the peak amplitude of nicotine-induced currents in chromaffin cells or in human embryonic kidney cells ectopically expressing functional neuronal α3β4α5 acetylcholine receptors (AChRs). Conversely, the phosphotyrosine phosphatase inhibitor, sodium vanadate, or expression of mutationally activated c-Src resulted in enhanced current amplitudes. These results suggest that SFKs and putative phosphotyrosine phosphatases regulate the activity of AChRs by opposing actions. This proposed model was supported further by the findings that SFKs physically associate with the receptor and that the AChR is tyrosine-phosphorylated.