Subcellular localization of γ-aminobutyric acid type A receptors is determined by receptor β subunits

?-aminobutyric acid type A (GABA(A)) receptors are the major sites of fast synaptic inhibition in the brain. They are constructed from four subunit classes with multiple members: a(1-6), ß(1-4), ?(1-4), and d(1). The contribution of subunit diversity in determining receptor subcellular targeting was examined in polarized Madin-Darby canine kidney (MDCK) cells. Significant detection of cell surface homomeric receptor expression by a combination of both immunological and electrophysiological methodologies was only found for the ß3 subunit. Expression of a/ß binary combinations resulted in a nonpolarized distribution for a1/ß1 complexes, but specific basolateral targeting of both a1ß2 and a1ß3 complexes. The polarized distribution of these a/ß complexes was unaffected by the presence of the ?2S subunit. Interestingly, delivery of receptors containing the ß3 subunit to the basolateral domain occurs via the apical surface. These results show that ß subunits can selectively target GABA(A) receptors to distinct cellular locations. Changes in the spatial and temporal expression of ß- subunit isoforms may therefore provide a mechanism for relocating GABA(A) receptor function between distinct neuronal domains. Given the critical role of these receptors in mediating synaptic inhibition, the contribution of different ß subunits in GABA(A) receptor function, may have implications in neuronal development and for receptor localization/clustering.