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Bernhard BETTLER "Genetic Dissection of GABAB Receptor Signaling"

Abstract :


GABAB receptors are the G-protein coupled receptors for GABA, the predominant inhibitory neurotransmitter in the mammalian central nervous system.
GABAB receptors modulate synaptic transmission by controlling neurotransmitter release and by causing postsynaptic hyperpolarization. They are broadly expressed in the nervous system and have been implicated in a variety of neurological and psychiatric conditions. In heterologous cells, functional GABAB receptors are usually only observed upon co-expression of GABAB1a or GABAB1b with GABAB2 subunits, which provided compelling evidence for heteromerization among G-protein coupled receptors. Consistent with these in vitro observations, the GABAB1 subunits are also essential for all GABAB signaling in vivo; mice lacking GABAB1 subunits do not exhibit detectable electrophysiological, biochemical or behavioral responses to GABAB agonists. However, mice lacking the GABAB2 subunit still exhibit atypical electrophysiological GABAB responses. It is currently impossible to determine whether these atypical responses are of physiological relevance, but it clearly cannot be not ruled out that in vivo functional GABAB receptors lacking a GABAB2 subunit do exist.

So far the data only unequivocally support the existence of the two heteromeric GABAB(1a,2) and GABAB(1b,2) receptors. GABAB1a and GABAB1b, arise from the GABAB1 gene by differential promoter usage. The only molecular difference between GABAB1a and GABAB1b is a pair of N-terminal sushi repeats, a known protein-protein interaction motif that is specific for GABAB1a. None of the available GABAB compounds thus far allow distinguishing GABAB(1a,2) and GABAB(1b,2) receptors. It is therefore unknown, which physiological responses relate to which receptor subtype. It also remains unclear whether GABAB(1a,2) and GABAB(1b,2) receptors localize to excitatory or inhibitory terminals, or both. Similarly, it is unknown whether GABAB(1a,2) and GABAB(1b,2) are both expressed at postsynaptic sites. Using a knock-in approach, we generated GABAB1a-/- and GABAB1b-/- mice. These mice have allowed us to address the individual roles of GABAB(1a,2) and GABAB(1b,2) receptors. Moreover, data will be presented to support that GHB, a metabolite of GABA and drug of abuse, is exerting its physiological effects through activation of GABAB receptors.

 

Selected publications

Gassmann M, Haller C, Stoll Y, Abdel Aziz S, Biermann B, Mosbacher J, Kaupmann K, Bettler B.
The RXR-Type ER-Retention/Retrieval Signal of GABAB1 Requires Distant Spacing from the Membrane to Function.
Mol Pharmacol. 2005 Apr 1;
Mombereau C, Kaupmann K, Gassmann M, Bettler B, van der Putten H, Cryan JF.
Altered anxiety and depression-related behaviour in mice lacking GABAB(2) receptor subunits.
Neuroreport. 2005 Feb 28;16(3):307-10.
Gassmann M, Shaban H, Vigot R, Sansig G, Bettler B. et al
Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice.
J Neurosci. 2004 Jul 7;24(27):6086-97.

Frédéric Nagy