Cytoplasmic domain of δ subunit is important for the extra-synaptic targeting of GABAA receptor subtypes

GABA(A) receptors (GABA(A)Rs) are hetero-pentameric chloride channels and the primary sites for fast synaptic inhibition. We have expressed recombinant gamma 2 and delta subunits of GABA(A)Rs in cultured hippocampal neurons to analyze the membrane targeting of synaptic and extrasynaptic GABA(A)Rs, a phenomenon not well understood. Our data demonstrate that the synaptic targeting of gamma 2-containing GABA(A)Rs (gamma 2-GABA(A)Rs) does not depend on the cytoplasmic loop of gamma 2 subunit, in parallel with previous findings, showing that the synaptic localization of gamma 2-GABA(A)Rs requires the TM4 domain of gamma 2 rather than the large cytoplasmic loop. On the other hand, we showed here that the extrasynaptic targeting of the delta-containing GABA(A)Rs (delta-GABA(A)Rs) depends on the cytoplasmic loop of delta subunit via an active or a passive mechanism. We also show that the amino acid sequences of delta loop is highly conserved across the whole span of vertebrate evolution suggesting an active role of delta loop in extrasynaptic targeting of corresponding receptor subtypes.