Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Characteristics of concatemeric GABA(A) receptors containing α4/δ subunits expressed in Xenopus oocytes.
Shu HJ, Bracamontes J, Taylor A, Wu K, Eaton MM, Akk G, Manion B, Evers AS, Krishnan K, Covey DF, Zorumski CF, Steinbach JH, Mennerick S.
???displayArticle.abstract???
GABA(A) receptors mediate both synaptic and extrasynaptic actions of GABA. In several neuronal populations, α4 and δ subunits are key components of extrasynaptic GABA(A) receptors that strongly influence neuronal excitability and could mediate the effects of neuroactive agents including neurosteroids and ethanol. However, these receptors can be difficult to study in native cells and recombinant δ subunits can be difficult to express in heterologous systems.We engineered concatemeric (fused) subunits to ensure δ and α4 subunit expression. We tested the pharmacology of the concatemeric receptors, compared with a common synaptic-like receptor subunit combination (α1 +β2 +γ2L), and with free-subunit α4/δ receptors, expressed in Xenopus oocytes.δ-β2 -α4 +β2-α4 cRNA co-injected into Xenopus oocytes resulted in GABA-gated currents with the expected pharmacological properties of α4/δ-containing receptors. Criteria included sensitivity to agonists of different efficacy, sensitivity to the allosteric activator pentobarbital, and modulation of agonist responses by DS2 (4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridine-3-yl benzamide; a δ-selective positive modulator), furosemide, and Zn(2+) . We used the concatemers to examine neurosteroid sensitivity of extrasynaptic-like, δ-containing receptors. We found no qualitative differences between extrasynaptic-like receptors and synaptic-like receptors in the actions of either negative or positive neurosteroid modulators of receptor function. Quantitative differences were explained by the partial agonist effects of the natural agonist GABA and by a mildly increased sensitivity to low steroid concentrations.The neurosteroid structure-activity profile for α4/δ-containing extrasynaptic receptors is unlikely to differ from that of synaptic-like receptors such as α1/β2/γ2-containing receptors.
Adkins,
alpha4beta3delta GABA(A) receptors characterized by fluorescence resonance energy transfer-derived measurements of membrane potential.
2001, Pubmed
Adkins,
alpha4beta3delta GABA(A) receptors characterized by fluorescence resonance energy transfer-derived measurements of membrane potential.
2001,
Pubmed Akk,
Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit.
2001,
Pubmed Akk,
Mechanisms of neurosteroid interactions with GABA(A) receptors.
2007,
Pubmed Akk,
Activation and modulation of concatemeric GABA-A receptors expressed in human embryonic kidney cells.
2009,
Pubmed Akk,
Activation of GABA(A) receptors containing the alpha4 subunit by GABA and pentobarbital.
2004,
Pubmed Akk,
Neuroactive steroids have multiple actions to potentiate GABAA receptors.
2004,
Pubmed Alexander,
Guide to Receptors and Channels (GRAC), 5th edition.
2011,
Pubmed Barker,
Potentiation of gamma-aminobutyric-acid-activated chloride conductance by a steroid anaesthetic in cultured rat spinal neurones.
1987,
Pubmed Barrera,
The subunit arrangement and assembly of ionotropic receptors.
2008,
Pubmed Baumann,
Individual properties of the two functional agonist sites in GABA(A) receptors.
2003,
Pubmed
,
Xenbase Baumann,
Forced subunit assembly in alpha1beta2gamma2 GABAA receptors. Insight into the absolute arrangement.
2002,
Pubmed
,
Xenbase Baur,
Diversity of structure and function of alpha1alpha6beta3delta GABAA receptors: comparison with alpha1beta3delta and alpha6beta3delta receptors.
2010,
Pubmed
,
Xenbase Baur,
Benzodiazepines affect channel opening of GABA A receptors induced by either agonist binding site.
2005,
Pubmed
,
Xenbase Belelli,
Extrasynaptic GABAA receptors: form, pharmacology, and function.
2009,
Pubmed Boileau,
The short splice variant of the gamma 2 subunit acts as an external modulator of GABA(A) receptor function.
2010,
Pubmed Bollan,
The promiscuous role of the epsilon subunit in GABAA receptor biogenesis.
2008,
Pubmed
,
Xenbase Borghese,
Studies of ethanol actions on recombinant delta-containing gamma-aminobutyric acid type A receptors yield contradictory results.
2007,
Pubmed Borghese,
The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol.
2006,
Pubmed
,
Xenbase Bracamontes,
Steroid interaction with a single potentiating site is sufficient to modulate GABA-A receptor function.
2009,
Pubmed
,
Xenbase Bracamontes,
Occupation of either site for the neurosteroid allopregnanolone potentiates the opening of the GABAA receptor induced from either transmitter binding site.
2011,
Pubmed
,
Xenbase Brickley,
Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABAA receptors.
1996,
Pubmed Brown,
Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors.
2002,
Pubmed Caraiscos,
Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane.
2004,
Pubmed Chandra,
GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol.
2006,
Pubmed Cope,
GABAA receptor-mediated tonic inhibition in thalamic neurons.
2005,
Pubmed Coulter,
Functional regulation of the dentate gyrus by GABA-mediated inhibition.
2007,
Pubmed Ebert,
Molecular pharmacology of gamma-aminobutyric acid type A receptor agonists and partial agonists in oocytes injected with different alpha, beta, and gamma receptor subunit combinations.
1994,
Pubmed
,
Xenbase Eisenman,
Activation-dependent properties of pregnenolone sulfate inhibition of GABAA receptor-mediated current.
2003,
Pubmed
,
Xenbase Farrant,
Variations on an inhibitory theme: phasic and tonic activation of GABA(A) receptors.
2005,
Pubmed Glykys,
Which GABA(A) receptor subunits are necessary for tonic inhibition in the hippocampus?
2008,
Pubmed Glykys,
A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol.
2007,
Pubmed Han,
Neurosteroid analogues. 4. The effect of methyl substitution at the C-5 and C-10 positions of neurosteroids on electrophysiological activity at GABAA receptors.
1996,
Pubmed Hemmings,
Emerging molecular mechanisms of general anesthetic action.
2005,
Pubmed Herd,
The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells.
2008,
Pubmed Hosie,
Conserved site for neurosteroid modulation of GABA A receptors.
2009,
Pubmed Houston,
Distinct regulation of beta2 and beta3 subunit-containing cerebellar synaptic GABAA receptors by calcium/calmodulin-dependent protein kinase II.
2008,
Pubmed Katona,
Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens.
2008,
Pubmed Kaur,
Unanticipated structural and functional properties of delta-subunit-containing GABAA receptors.
2009,
Pubmed
,
Xenbase Li,
Natural and enantiomeric etiocholanolone interact with distinct sites on the rat alpha1beta2gamma2L GABAA receptor.
2007,
Pubmed Meera,
Alcohol- and alcohol antagonist-sensitive human GABAA receptors: tracking δ subunit incorporation into functional receptors.
2010,
Pubmed Meera,
Molecular basis for the high THIP/gaboxadol sensitivity of extrasynaptic GABA(A) receptors.
2011,
Pubmed
,
Xenbase Meera,
Etomidate, propofol and the neurosteroid THDOC increase the GABA efficacy of recombinant alpha4beta3delta and alpha4beta3 GABA A receptors expressed in HEK cells.
2009,
Pubmed Mihalek,
Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout mice.
1999,
Pubmed Mortensen,
Distinct activities of GABA agonists at synaptic- and extrasynaptic-type GABAA receptors.
2010,
Pubmed Nagaya,
Two gamma2L subunit domains confer low Zn2+ sensitivity to ternary GABA(A) receptors.
2001,
Pubmed Nakashima,
Blockade of Ba2+ current through human alpha1E channels by two steroid analogs, (+)-ACN and (+)-ECN.
1999,
Pubmed Nusser,
Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells.
2002,
Pubmed Reddy,
Neurosteroids: endogenous role in the human brain and therapeutic potentials.
2010,
Pubmed Sack,
How to validate a heteromeric ion channel drug target: assessing proper expression of concatenated subunits.
2008,
Pubmed Shen,
Pregnenolone sulfate modulates inhibitory synaptic transmission by enhancing GABA(A) receptor desensitization.
2000,
Pubmed Sigel,
Use of concatamers to study GABAA receptor architecture and function: application to delta-subunit-containing receptors and possible pitfalls.
2009,
Pubmed Smart,
GABAA receptors are differentially sensitive to zinc: dependence on subunit composition.
1991,
Pubmed Stell,
Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABAA receptors.
2003,
Pubmed Stell,
Receptors with different affinities mediate phasic and tonic GABA(A) conductances in hippocampal neurons.
2002,
Pubmed Stórustovu,
Pharmacological characterization of agonists at delta-containing GABAA receptors: Functional selectivity for extrasynaptic receptors is dependent on the absence of gamma2.
2006,
Pubmed
,
Xenbase Sundstrom-Poromaa,
Hormonally regulated alpha(4)beta(2)delta GABA(A) receptors are a target for alcohol.
2002,
Pubmed
,
Xenbase Todorovic,
5beta-reduced neuroactive steroids are novel voltage-dependent blockers of T-type Ca2+ channels in rat sensory neurons in vitro and potent peripheral analgesics in vivo.
2004,
Pubmed Wafford,
Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus.
2009,
Pubmed Wafford,
Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit.
1996,
Pubmed
,
Xenbase Wagoner,
Stoichiometry of expressed alpha(4)beta(2)delta gamma-aminobutyric acid type A receptors depends on the ratio of subunit cDNA transfected.
2010,
Pubmed
,
Xenbase Wallner,
Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans.
2003,
Pubmed
,
Xenbase Wang,
3beta -hydroxypregnane steroids are pregnenolone sulfate-like GABA(A) receptor antagonists.
2002,
Pubmed
,
Xenbase Wei,
Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus.
2003,
Pubmed White,
Pretty subunits all in a row: using concatenated subunit constructs to force the expression of receptors with defined subunit stoichiometry and spatial arrangement.
2006,
Pubmed Wittmer,
Enantioselectivity of steroid-induced gamma-aminobutyric acidA receptor modulation and anesthesia.
1996,
Pubmed
,
Xenbase Wohlfarth,
Enhanced neurosteroid potentiation of ternary GABA(A) receptors containing the delta subunit.
2002,
Pubmed
