Functional role of the GABA(A) receptor epsilon subunit

Recombinant studies characterizing the human GABAA receptor epsilon subunit reveal a reduced sensitivity of epsilon-containing receptors to Zn 2+, a diminished sensitivity of epsilon-containing receptors to modulation by anesthetics and the appearance of spontaneous gating in epsilon-containing receptors.{09}The physiological role of the epsilon subunit remains unknown.; The cloning of cDNAs encoding two rodent epsilon subunit isoforms allow for analysis of the subunit's physiological role. Electrophysiological studies show that the epsilonr subunit is similar to its human orthologue in that it causes the appearance of spontaneous gating, as well as reducing the ability of Zn2+ and anesthetics to modulate the GABA-evoked current. No functional contributions of the alternative transcript epsilon rL were observed in this study.; The epsilon subunit is localized to the Nucleus Tractus Solitarius (NTS), locus coeruleus (LC), hypothalamus and hippocampas. Pharmacological analysis of GABAA receptors activated by exogenous GABA in NTS neurons was consistent with them having the alphabetaepsilon or alphabetagammaepsilon combination. While not conclusive, my findings in NTS neurons suggest that the epsilon subunit contributes to extrasynaptic receptors.; Extrasynaptic receptors mediate tonic current. I describe a mechanism of tonic inhibition through GABA-independent constitutive GABAA receptor gating in hippocampal pyramidal neurons, a mechanism that accounts for the unusual pharmacology of tonic currents in these cells. Picrotoxin inhibits tonic current in the absence of exogenous GABA, while the competitive GABAA antagonist SR-95531 (gabazine, GBZ) does not. By contrast, GBZ abolishes IPSCs and currents activated by exogenous GABA, demonstrating that all GABA-dependent gating in pyramidal neurons can be blocked by GBZ. Functional glycine receptors present in cultured hippocampal neurons did not contribute to the tonic current. Immunohistochemistry reveals that pyramidal neurons express extrasynaptic epsilon subunits. Over-expression of the epsilon subunit in pyramidal neurons increases GBZ-resistant tonic current without affecting IPSCs. I propose that constitutively active extrasynaptic receptors containing the epsilon subunit mediate GABA-independent tonic inhibition in hippocampal pyramidal neurons.; I have shown that the epsilon subunit is present in rodent neurons and that it contributes to the functional properties of these receptors. It is reasonable to assume that the epsilon subunit will impact the physiology of neurons in which it is expressed.