Separate Domains for Desensitization of GABA ρ1 and β2 Subunits Expressed in Xenopus Oocytes
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Desensitization of ligand-gated receptor channels is an intrinsic feedback mechanism and prevents the receptor/channels from becoming overly activated thereby maintaining biological function of the nervous system. Desensitization also plays an important role in neuronal plasticity. By taking advantage of biophysical and pharmacological diversities of GABA β2 subunits from the brain and ρ1 subunits from the retina, structural determinants that confer agonist-induced desensitization were identified. A synthetic chimeric receptor/channel was created from the β2 and ρ1 subunits for this investigation. The chimera was constructed from the extracellular N-domain of the β2 subunit, extending from the amino terminus to the beginning region of the M1 transmembrane segment, and from the C-domain of the ρ1 subunit extending from the M1 transmembrane segment to the carboxyl terminus. The C-domain region included the M1 to M4 transmembrane regions and the large intracellular loop between the M3 and M4 transmembrane segments. Homo-oligomeric GABA β2, ρ1, and β2/ρ1 chimeric receptor/channels were individually expressed in Xenopus oocytes, and the desensitization characteristics attributable to each type of subunit were compared. Results from the present study reveal that motifs in the amino-terminal and carboxyl-terminal domains of the β2 subunit conferred the agonist-induced desensitization; chloroform modulation was linked to specific phases of the GABA-activated current decay.
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