Unanticipated structural and functional properties of delta-subunit-containing GABAA receptors

Kaur, Kuldeep H; Baur, Roland; Sigel, Erwin (2009). Unanticipated structural and functional properties of delta-subunit-containing GABAA receptors. Journal of biological chemistry, 284(12), pp. 7889-96. Bethesda, Md.: American Society for Biochemistry and Molecular Biology 10.1074/jbc.M806484200

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GABA(A) receptors mediate inhibitory neurotransmission in the mammalian brain via synaptic and extrasynaptic receptors. The delta (delta)-subunit-containing receptors are expressed exclusively extra-synaptically and mediate tonic inhibition. In the present study, we were interested in determining the architecture of receptors containing the delta-subunit. To investigate this, we predefined the subunit arrangement by concatenation. We prepared five dual and three triple concatenated subunit constructs. These concatenated dual and triple constructs were used to predefine nine different GABA(A) receptor pentamers. These pentamers composed of alpha(1)-, beta(3)-, and delta-subunits were expressed in Xenopus oocytes and maximal currents elicited in response to 1 mm GABA were determined in the presence and absence of THDOC (3alpha, 21-dihydroxy-5alpha-pregnane-20-one). beta(3)-alpha(1)-delta/alpha(1)-beta(3) and beta(3)-alpha(1)-delta/beta(3)-alpha(1) resulted in the expression of large currents in response to GABA. Interestingly, the presence of the neurosteroid THDOC uncovered alpha(1)-beta(3)-alpha(1)/beta(3)-delta receptors, additionally. The functional receptors were characterized in detail using the agonist GABA, THDOC, Zn(2+), and ethanol and their properties were compared with those of non-concatenated alpha(1)beta(3) and alpha(1)beta(3)delta receptors. Each concatenated receptor isoform displayed a specific set of properties, but none of them responded to 30 mm ethanol. We conclude from the investigated receptors that delta can assume multiple positions in the receptor pentamer. The GABA dose-response properties of alpha(1)-beta(3)-alpha(1)/beta(3)-delta and beta(3)-alpha(1)-delta/alpha(1)-beta(3) match most closely the properties of non-concatenated alpha(1)beta(3)delta receptors. Furthermore, we show that the delta-subunit can contribute to the formation of an agonist site in alpha(1)-beta(3)-alpha(1)/beta(3)-delta receptors.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
UniBE Contributor:	Baur, Roland, Sigel, Erwin
ISSN:	0021-9258
Publisher:	American Society for Biochemistry and Molecular Biology
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:12
Last Modified:	05 Dec 2022 14:22
Publisher DOI:	10.1074/jbc.M806484200
PubMed ID:	19141615
Web of Science ID:	000264195600050
URI:	https://boris.unibe.ch/id/eprint/31634 (FactScience: 196265)