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The C-Terminal Domains of the GABA B Receptor Subunits Mediate Intracellular Trafficking But Are Not Required for Receptor Signaling

2001; Society for Neuroscience; Volume: 21; Issue: 4 Linguagem: Inglês

10.1523/jneurosci.21-04-01203.2001

1529-2401

Andrew R. Calver, Melanie J. Robbins, Christophe Cosio, Simon Q.J. Rice, Adam J. Babbs, Warren D. Hirst, Izzy Boyfield, Martyn Wood, Robert B. Russell, Gary Price, Andrés Couve, Stephen J. Moss, Menelas N. Pangalos,

Ion channel regulation and function

GABA B receptors are G-protein-coupled receptors that mediate slow synaptic inhibition in the brain and spinal cord. These receptors are heterodimers assembled from GABA B1 and GABA B2 subunits, neither of which is capable of producing functional GABA B receptors on homomeric expression. GABA B1, although able to bind GABA, is retained within the endoplasmic reticulum (ER) when expressed alone. In contrast, GABA B2 is able to access the cell surface when expressed alone but does not couple efficiently to the appropriate effector systems or produce any detectable GABA-binding sites. In the present study, we have constructed chimeric and truncated GABA B1 and GABA B2 subunits to explore further GABA B receptor signaling and assembly. Removal of the entire C-terminal intracellular domain of GABA B1 results in plasma membrane expression without the production of a functional GABA B receptor. However, coexpression of this truncated GABA B1 subunit with either GABA B2 or a truncated GABA B2 subunit in which the C terminal has also been removed is capable of functional signaling via G-proteins. In contrast, transferring the entire C-terminal tail of GABA B1 to GABA B2 leads to the ER retention of the GABA B2 subunit when expressed alone. These results indicate that the C terminal of GABA B1 mediates the ER retention of this protein and that neither of the C-terminal tails of GABA B1 or GABA B2 is an absolute requirement for functional coupling of heteromeric receptors. Furthermore although GABA B1 is capable of producing GABA-binding sites, GABA B2 is of central importance in the functional coupling of heteromeric GABA B receptors to G-proteins and the subsequent activation of effector systems.