Evidence for oligomerization between GABAB receptors and GIRK channels containing the GIRK1 and GIRK3 subunits

被引:43
作者
Ciruela, Francisco [1 ]
Fernandez-Duenas, Victor [1 ]
Sahlholm, Kristoffer [2 ]
Fernandez-Alacid, Laura [3 ]
Nicolau, Joel C. [3 ]
Watanabe, Masahiko [4 ]
Lujan, Rafael [3 ]
机构
[1] Univ Barcelona, Univ IDIBELL, Fac Med Bellvitge, Dept Patol & Terapeut Expt,Unitat Farmacol 4102, Barcelona 08907, Spain
[2] Karolinska Inst, Dept Neurosci, Stockholm, Sweden
[3] Univ Castilla La Mancha, Fac Med, Inst Invest Discapacidades Neurol IDINE, Dept Ciencias Med, Albacete 02006, Spain
[4] Hokkaido Univ, Sch Med, Dept Anat, Sapporo, Hokkaido 060, Japan
关键词
cerebellum; electron microscopy; G protein-coupled receptors; immunohistochemistry; K plus channels; rat; receptor-channel oligomerization; GATED POTASSIUM CHANNELS; RECTIFYING K+-CHANNEL; PROTEIN-COUPLED-RECEPTOR; METABOTROPIC GLUTAMATE RECEPTORS; BETA-GAMMA-SUBUNITS; INWARD RECTIFIER; SIGNALING COMPLEX; RAT-BRAIN; FUNCTIONAL EXPRESSION; SPLICE VARIANTS;
D O I
10.1111/j.1460-9568.2010.07356.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The stimulation of inhibitory neurotransmitter receptors, such as gamma-aminobutyric acid type B (GABA(B)) receptors, activates G protein-gated inwardly-rectifying K+ (GIRK) channels, which influence membrane excitability. There is now evidence suggesting that G protein-coupled receptors and G protein-gated inwardly-rectifying K+ [GIRK/family 3 of inwardly-rectifying K+ (Kir3)] channels do not diffuse freely within the plasma membrane, but instead there are direct protein-protein interactions between them. Here, we used bioluminescence resonance energy transfer, co-immunoprecipitation, confocal and electron microscopy techniques to investigate the oligomerization of GABA(B) receptors with GIRK channels containing the GIRK3 subunit, whose contribution to functional channels is still unresolved. Co-expression of GABA(B) receptors and GIRK channels in human embryonic kidney-293 cells in combination with co-immunoprecipitation experiments established that the metabotropic receptor forms stable complexes with GIRK channels. Using bioluminescence resonance energy transfer, we have shown that, in living cells under physiological conditions, GABA(B) receptors interact directly with GIRK1/GIRK3 heterotetramers. In addition, we have provided evidence that the receptor-effector complexes are also found in vivo and identified that the cerebellar granule cells are one neuron population where the interaction probably takes place. Altogether, our data show that signalling complexes containing GABA(B) receptors and GIRK channels are formed shortly after biosynthesis, probably in the endoplasmic reticulum and/or endoplasmic reticulum/Golgi apparatus complex, suggesting that this might be a general feature of receptor-effector ion channel signal transduction and supporting a channel-forming role for the GIRK3 subunit.
引用
收藏
页码:1265 / 1277
页数:13
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