Modulation of GABAA receptors by tyrosine phosphorylation.
gamma-Aminobutyric acid type-A (GABAA) receptors are the major sites of fast synaptic inhibition in the brain. They are presumed to be pentameric heteroligomers assembled from four classes of subunits with multiple members: alpha (1-6), beta (1-3), gamma (1-3) and delta (1). Here, GABAA receptors consisting of alpha 1, beta 1 and gamma 2L subunits, coexpressed in mammalian cells with the tyrosine kinase vSRC (the transforming gene product of the Rous sarcoma virus), were phosphorylated on tyrosine residues within the gamma 2L and beta 1 subunits. Tyrosine phosphorylation enhanced the whole-cell current induced by GABA. Site-specific mutagenesis of two tyrosine residues within the predicted intracellular domain of the gamma 2L subunit abolished tyrosine phosphorylation of this subunit and eliminated receptor modulation. A similar modulation of GABAA receptor function was observed in primary neuronal cultures. As GABAA receptors are critical in mediating fast synaptic inhibition, such a regulation by tyrosine kinases may therefore have profound effects on the control of neuronal excitation.
Moss
S J
SJ
MRC Laboratory of Molecular Cell Biology, University College London, UK.
Gorrie
G H
GH
Amato
A
A
Smart
T G
TG
D000595:Amino Acid Sequence; D002460:Cell Line; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017783:Superior Cervical Ganglion / Q000166:cytology; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism*
D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D014443:Tyrosine