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A COMPARISON OF THE PHARMACOLOGICAL PROPERTIES OF RECOMBINANT HUMAN AND RAT α 1 β 2 γ 2 L GABA A RECEPTORS IN XENOPUS OOCYTES
Author(s) -
Rahman Mozibur,
Borra Vijaya B,
Isaksson Monica,
Johansson IngaMaj,
Ragagnin Gianna,
Bäckström Torbjörn,
Wang MingDe
Publication year - 2008
Publication title -
clinical and experimental pharmacology and physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 103
eISSN - 1440-1681
pISSN - 0305-1870
DOI - 10.1111/j.1440-1681.2008.04946.x
Subject(s) - neuroactive steroid , receptor , gabaa receptor , endocrinology , gabab receptor , allosteric regulation , medicine , pregnenolone , chemistry , pharmacology , biology , biochemistry , steroid , hormone
SUMMARY1 In the present study, we compared the pharmacology, particularly neurosteroid modulation of the GABA A receptor, between human and rat a 1 b 2 g 2 L GABA A receptors and between human receptors containing the long ( L ) and short ( S ) forms of the g 2 ‐subunit. 2 We observed that maximum responses to GABA were significantly higher with the human a 1 b 2 g 2 L receptor compared with the rat receptor. In terms of neurosteroid modulation, increases in the EC 15 response to GABA induced by 3a‐OH‐5b‐pregnan‐20‐one (3a5bP), 5a‐androstane‐3a,17b‐diol (3a5aADL) and 5a‐pregnane‐3a,20b‐diol (3a5a‐diol) were significantly greater for the rat compared with the human receptor. Responses to 30 mmol/L GABA were inhibited by 3b‐OH‐5a‐pregnan‐20‐one (UC1010) and 5b‐pregnan‐3b,20(R)‐diol (UC1020) to a greater degree for human and rat receptors, respectively. Responses to GABA + 3a5aTHDOC were inhibited by 5a‐pregnan‐3b,20(S)‐diol (UC1019) and pregnenolone sulphate to a greater degree for human and rat receptors, respectively. 3 The GABA dose–response curves for human a 1 b 2 g 2 S and a 1 b 2 g 2 L receptors were identical. However, the maximum GABA‐evoked current, the direct gating effect of pentobarbital and the allosteric potentiation of the GABA EC 15 response by 3a5aTHDOC and 3a5bP were significantly higher with a 1 b 2 g 2 S than a 1 b 2 g 2 L receptors. Inhibition of the response to 30 mmol/L GABA by UC1010 and UC1020 was greater for a 1 b 2 g 2 L and a 1 b 2 g 2 S receptors, respectively. Inhibition of responses to 3a5aTHDOC + GABA by UC1019 and UC1010 was significantly higher for a 1 b 2 g 2 L receptors. 4 In conclusion, the site of activation by GABA and neurosteroid modulation differ between human and rat a 1 b 2 g 2 L receptors, as well as between human receptors containing the L and S splice variants of the g 2 ‐subunit.