Toward Understanding Functional Properties and Subunit Arrangement of α4β2δ γ-Aminobutyric Acid, Type A (GABAA) Receptors.

Wongsamitkul, Nisa; Baur, Roland; Sigel, Erwin (2016). Toward Understanding Functional Properties and Subunit Arrangement of α4β2δ γ-Aminobutyric Acid, Type A (GABAA) Receptors. Journal of biological chemistry, 291(35), pp. 18474-18483. American Society for Biochemistry and Molecular Biology 10.1074/jbc.M116.738906

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GABAA receptors are pentameric ligand-gated channels mediating inhibitory neurotransmission in the CNS. α4βxδ GABAA receptors are extrasynaptic receptors important for tonic inhibition. The functional properties and subunit arrangement of these receptors are controversial. We predefined subunit arrangement by using subunit concatenation. α4, β2, and δ subunits were concatenated to dimeric, trimeric, and, in some cases, pentameric subunits. We constructed in total nine different receptor pentamers in at least two different ways and expressed them in Xenopus oocytes. The δ subunit was substituted in any of the five positions in the α1β2 receptor. In addition, we investigated all receptors with the 2:2:1 subunit stoichiometry for α4, β2, and δ. Several functional receptors were obtained. Interestingly, all of these receptors had very similar EC50 values for GABA in the presence of the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC). All functional receptors containing δ subunits were sensitive to 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide (DS2). Moreover, none of the receptors was affected by ethanol up to 30 mm These properties recapitulate those of non-concatenated receptors expressed from a cRNA ratio of 1:1:5 coding for α4, β2, and δ subunits. We conclude that the subunit arrangement of α4β2δ GABAA receptors is not strongly predefined but is mostly satisfying the 2:2:1 subunit stoichiometry for α4, β2, and δ subunits and that several subunit arrangements result in receptors with similar functional properties tuned to physiological conditions.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Wongsamitkul, Nisa; Baur, Roland and Sigel, Erwin

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

0021-9258

Publisher:

American Society for Biochemistry and Molecular Biology

Language:

English

Submitter:

Barbara Järmann-Bangerter

Date Deposited:

19 Apr 2017 16:24

Last Modified:

27 Aug 2017 02:30

Publisher DOI:

10.1074/jbc.M116.738906

PubMed ID:

27382064

Uncontrolled Keywords:

GABA; GABAA receptor; Xenopus; electrophysiology; ion channel; neurotransmitter receptor; γ-aminobutyric acid type A; δ subunit

BORIS DOI:

10.7892/boris.94116

URI:

https://boris.unibe.ch/id/eprint/94116

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