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J Biol Chem, Vol. 273, Issue 49, 32595-32601, December 4, 1998

Activation of Protein Kinase C Induces -Aminobutyric Acid Type A Receptor Internalization in Xenopus Oocytes

Richard Chapell, Orlando F. Bueno, Xavier Alvarez-Hernandez^§, Lucy C. Robinson^¶, and Nancy J. Leidenheimer

From the Departments of  Pharmacology, ^§ Medicine, and ^¶ Biochemistry, Louisiana State University Medical Center, Shreveport, Louisiana 71130

The inhibition of -aminobutyric acid (GABA)-gated chloride currents by the protein kinase C (PKC) activator 4-phorbol 12-myristate 13-acetate (PMA) was investigated using recombinant human GABA_A receptors expressed in Xenopus oocytes. PMA (5 nM) reduced the GABA response in oocytes expressing the 122L receptor construct, as measured by the two-electrode voltage-clamp method. GABA responses declined to approximately 25% of their pretreatment value within 45 min. GABA responses in oocytes expressing a receptor construct from which the known PKC phosphorylation sites were absent, 12(S410A), were comparably inhibited. Phorbol 12-monomyristate (PMM; 5 nM), which does not activate PKC, did not alter the GABA response in either construct, while the PKC inhibitor calphostin C (0.5 µM) prevented the PMA effect. To further investigate PMA inhibition of the GABA response, a GABA_A receptor 1 subunit/green fluorescent protein (GFP) chimera (1GFP) was used to visualize GABA_A receptor distribution. Similar to the wild type constructs, PMA robustly decreased GABA responses in oocytes expressing 1GFP22L and 1GFP2(S410A) receptor constructs. Following PMA treatment, GFP fluorescence in the oocyte plasma membrane was decreased to approximately 45% of the pretreatment values indicating GABA_A receptor internalization. This effect of PMA was prevented by calphostin C and was not produced by PMM. Experiments with bd24, a monoclonal antibody which recognizes an extracellular epitope of the 1 subunit, were used to demonstrate that PMA, but not PMM, decreases 1 subunit immunoreactivity in the plasma membrane of intact oocytes expressing the 122L construct, thus confirming the results obtained with the chimeric receptor. It is concluded that, in Xenopus oocytes, PMA induces an internalization of the GABA_A receptor through PKC-mediated phosphorylation of an unidentified protein(s) and that this contributes to the decrease in electrophysiological responses to GABA following PKC activation.

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