期刊
JOURNAL OF NEUROSCIENCE
卷 24, 期 27, 页码 6086-6097出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5635-03.2004
关键词
GABA; GPCR; G-protein; heterodimerization; metabotropic; trafficking
GABA(B) receptors mediate slow synaptic inhibition in the nervous system. In transfected cells, functional GABA(B) receptors are usually only observed after coexpression of GABA(B(1)) and GABA(B(2)) subunits, which established the concept of heteromerization for G-protein-coupled receptors. In the heteromeric receptor, GABA(B(1)) is responsible for binding of GABA, whereas GABA(B(2)) is necessary for surface trafficking and G-protein coupling. Consistent with these in vitro observations, the GABA(B(1)) subunit is also essential for all GABA(B) signaling in vivo. Mice lacking the GABA(B(1)) subunit do not exhibit detectable electrophysiological, biochemical, or behavioral responses to GABA(B) agonists. However, GABA(B(1)) exhibits a broader cellular expression pattern than GABA(B(2)), suggesting that GABA(B(1)) could be functional in the absence of GABA(B(2)). We now generated GABA(B(2))-deficient mice to analyze whetherGABA(B(1)) has the potential to signal without GABA(B(2)) in neurons. We show that GABA(B(2))(-/-) mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABA(B(1))(-/-) mice. This clearly demonstrates that the lack of heteromeric GABA(B(1,2)) receptors underlies these phenotypes. To our surprise and in contrast to GABA(B(1))(-/-) mice, we still detect atypical electrophysiological GABA(B) responses in hippocampal slices of GABA(B(2))(-/-) mice. Furthermore, in the absence of GABA(B(2)), the GABA(B(1)) protein relocates from distal neuronal sites to the soma and proximal dendrites. Our data suggest that association of GABA(B(2)) with GABA(B(1)) is essential for receptor localization in distal processes but is not absolutely necessary for signaling. It is therefore possible that functional GABA(B) receptors exist in neurons that naturally lack GABA(B(2)) subunits.
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