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Two 2L subunit domains confer low Zn²⁺ sensitivity to ternary GABA_A receptors

Naomi Nagaya * and Robert L. Macdonald *†

1. The sensitivity of GABA_A receptors (GABARs) to Zn²⁺ inhibition depends on subunit composition. The predominant neuronal forms of mammalian GABARs, and , are differentially sensitive to Zn²⁺ inhibition; receptors are substantially less sensitive than receptors. Recently, functional domains involved in Zn²⁺ sensitivity have been identified in and subunits. Our aim in the present study was to localize functional domains of low Zn²⁺ sensitivity within 2L subunits.

2. Chimeric subunits were constructed by progressively replacing the rat 2L subunit sequence with that of the rat subunit sequence. Whole-cell currents were recorded from mouse L929 fibroblasts coexpressing wild-type rat 1 and 3 subunits with a chimeric -2L subunit.

3. Unlike and subunits, the 2L subunit was found to contain a determinant of low Zn²⁺ sensitivity in the N-terminal extracellular region. In addition, we identified determinants in the M2 segment and the M2-M3 loop of the 2L subunit that are homologous to those found in and subunits.

4. We postulate that the interface between the latter two domains, which may form the outer vestibule of the channel, represents a single functional domain modulating Zn²⁺ sensitivity. Thus, the Zn²⁺ sensitivity of ternary GABARs appears to be determined by two functional domains, one in the N-terminal extracellular region and one near the outer mouth of the channel.

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