Redistribution of GABA_B(1)Protein and Atypical GABA_BResponses in GABA_B(2)-Deficient Mice

Abstract

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-proteincoupled 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 whether GABA B(1) has the potential to signal without GABA B(2) in neurons. We show that GABA B(2) Ϫ/Ϫ mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity, and severe memory impairment, analogous to GABA B(1) Ϫ/Ϫ 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) Ϫ/Ϫ mice, we still detect atypical electrophysiological GABA B responses in hippocampal slices of GABA B(2) Ϫ/Ϫ 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.

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

“…In this context, GABA B receptors were found to be highly expressed in the limbic areas (McDonald et al, 2004). Additionally, GABA B receptors on glutamatergic terminals were shown to reduce glutamatergic transmission in the hippocampus (Gassmann et al, 2004). Further investigations confirmed the presynaptic localization of a considerable fraction of the GABA B receptors formed by GABA B1a and GABA B2 subunits (Biermann et al, 2010).…”

Sushi domains confer distinct trafficking profiles on GABA B receptors

“…The SDs in R1a are noted for their importance in the differential subcellular targeting of R1aR2 over R1bR2 receptors (13,15). The SDs form an axonal targeting signal for the preferential transport of R1aR2 receptors, although R1aR2 and R1bR2 receptors can also be found in the cell soma and dendrites (19).…”

“…GIRK cells and hippocampal neurons (14)(15)(16)(17)(18)(19)(20)(21) were imaged and analyzed as described previously (20) using ImageJ (version 1.40g) and Origin (version 6; OriginLab).…”

“…Heteromers formed from R1aR2 and R1bR2 are thought to play distinct roles in neurotransmission (13)(14)(15)(16)(17)(18), with R1aR2 contributing to presynaptic heteroreceptors to inhibit neurotransmitter release, although both R1aR2 and R1bR2 populate postsynaptic membranes to dampen excitability. These heteromeric subtypes exhibit different subcellular compartmentalization with the SDs acting as an axonal-targeting sequence to deliver R1aR2 more efficiently to axons compared with R1bR2 (19).…”

The GABAB Receptor-Positive Modulator GS39783 and the GABAB Receptor Agonist Baclofen Attenuate the Reward-Facilitating Effects of Cocaine: Intracranial Self-Stimulation Studies in the Rat

“…Despite the identification of GABA B receptors over 20 years ago (Bowery et al, 1980), the molecular identity of this receptor has only recently been elucidated (Kaupmann et al, 1997). GABA B receptors form heterodimers comprised of GABA B(1) , of which there are at least two known functional splice variants, GABA B(1a) and GABA B(1b) , and GABA B(2) subunits, both of which are necessary for formation of functionally active receptors (Calver et al, 2002; but see, Gassmann et al, 2004). GABA B receptors are located both pre-and postsynaptically where they modulate, both neurotransmitter release and inhibitory postsynaptic potentials, respectively.…”