Regulation of the neuronal nicotinic acetylcholine receptor by SRC family tyrosine kinases.
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 alpha3beta4alpha5 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.
Wang
Kan
K
Department of Microbiology and Cancer Center, University of Virginia, Charlottesville, VA 22908, USA.
Hackett
John T
JT
Cox
Michael E
ME
Van Hoek
Monique
M
Lindstrom
Jon M
JM
Parsons
Sarah J
SJ
D002460:Cell Line; D019439:Chromaffin Cells / Q000378:metabolism; D006801:Humans; D009417:Nerve Tissue / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011940:Receptor Aggregation; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism*
D011978:Receptors, Nicotinic; D019061:src-Family Kinases