Modulation of GABAA receptors by tyrosine phosphorylation

Abstract

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.

Interaction of Calcineurin and Type-A GABA Receptor γ2Subunits Produces Long-Term Depression at CA1 Inhibitory Synapses

“…The internal versus surface expression of GABA A receptors in the postsynaptic sites needs to be examined to determine CaN-mediated GABA A receptor trafficking to and from the cell surface that is therefore likely to be an important mechanism for expression of LTD at inhibitory synapses. In addition to adaptin, there has been a report that tyrosine kinase Src modulates neuronal as well as recombinant GABA A receptors to enhance receptor channel activity (Moss et al, 1995). Src kinase also phosphorylates both Y 365 and Y 367 residues of the ␥ 2L (long form) subunit (Moss et al, 1995).…”

“…In addition to adaptin, there has been a report that tyrosine kinase Src modulates neuronal as well as recombinant GABA A receptors to enhance receptor channel activity (Moss et al, 1995). Src kinase also phosphorylates both Y 365 and Y 367 residues of the ␥ 2L (long form) subunit (Moss et al, 1995). By specifically blocking the association of Src with the GABA A receptor ␥ 2 subunit (Fig.…”

Inhibition of GABAASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

“…In this respect, there seems to be a time lag between elevation of [Ca 2ϩ ] i and BDNF-induced reduction of the amplitude of IPSCs, suggesting the involvement of activation of some signal cascade after the rise in [Ca 2ϩ ] i . GABA A receptor function is maintained by phosphorylation and disrupted by [Ca 2ϩ ] i elevation (Stelzer et al, 1988;Marchenko, 1991;Gyenes et al, 1994;Moss et al, 1995). In this respect, dephosphorylation induced by a Ca 2ϩ -dependent phosphatase may be involved in the downstream of BDNF-activated signal transduction and lead to the attenuation of GABA A response (Stelzer and Shi, 1994;Chen and Wong, 1995).…”

Inhibitory effects of genistein on ATP‐sensitive K+ channels in rabbit portal vein smooth muscle

“…Evidence has been accumulating for some years now that tyrosine kinases are involved in receptor-mediated current inhibition, and in contraction and cell-signalling (Williams, 1989;Tsuda. et al, 1991;Wijetunge et al, 1992;Huang et al, 1993;Hollenberg, 1994;Felder, 1995;Wang & Salter, 1994;Moss et al, 1995;Wijetunge & Hughes, 1995;Hatakeyama et al, 1996). These studies suggest tyrosine phosphorylation of tyrosine residues might be an important mechanism for channel regulation, in addition to the well-attested protein phosphorylation that occurs through serine/threonine kinases.…”

“…These studies suggest tyrosine phosphorylation of tyrosine residues might be an important mechanism for channel regulation, in addition to the well-attested protein phosphorylation that occurs through serine/threonine kinases. It has also been found that various channels can be phosphorylated by tyrosine kinase and the e ect inhibited by tyrosine kinase inhibitors (Huang et al, 1993;Moss et al, 1995;Lev et al, 1995;Swope et al, 1995).…”