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Α4βδ GABAA Receptors Are High-Affinity Targets for Γ

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Α4βδ GABAA Receptors Are High-Affinity Targets for Γ α4βδ GABAA receptors are high-affinity targets for γ-hydroxybutyric acid (GHB) Nathan Absaloma,1, Laura F. Eghornb,1, Inge S. Villumsenb, Nasiara Karima, Tina Bayb, Jesper V. Olsenc, Gitte M. Knudsend, Hans Bräuner-Osborneb, Bente Frølundb, Rasmus P. Clausenb, Mary Chebiba,2, and Petrine Wellendorphb,2 aFaculty of Pharmacy A15, University of Sydney, Sydney, New South Wales 2006, Australia; bDepartment of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2100 Copenhagen, Denmark; cNovo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; and dNeurobiology Research Unit and Center for Integrated Molecular Brain Imaging (Cimbi), Rigshospitalet and University of Copenhagen, 2100 Copenhagen, Denmark Edited by Leslie Lars Iversen, University of Oxford, Oxford, United Kingdom, and approved June 6, 2012 (received for review March 13, 2012) γ-Hydroxybutyric acid (GHB) binding to brain-specific high-affinity BnOPh-GHB) (8). Furthermore, several reports point to GHB- sites is well-established and proposed to explain both physiolog- induced effects that cannot be consequences of GABAB receptor ical and pharmacological actions. However, the mechanistic links activation alone: Fos expression studies with GHB indicate between these lines of data are unknown. To identify molecular a unique pattern of neuronal activation, which in several ways, is fi fi targets for speci c GHB high-af nity binding, we undertook pho- different from the pattern produced by the GABAB receptor tolinking studies combined with proteomic analyses and identified agonist baclofen (9). Numerous effects induced by GHB, including several GABAA receptor subunits as possible candidates. A subse- sedation, catalepsy (10), increased striatal dopamine release, quent functional screening of various recombinant GABAA recep- changes in EEG pattern (11), discriminative stimulus properties tors in Xenopus laevis oocytes using the two-electrode voltage (12), and reinforcing effects (13), are dose-dependently decreased clamp technique showed GHB to be a partial agonist at αβδ- but by pretreatment with the GHB receptor-specific ligand NCS-382. not αβγ-receptors, proving that the δ-subunit is essential for po- Additionally, ataxia seems to be mediated through the high-af- tency and efficacy. GHB showed preference for α4 over α(1,2,6)- finity GHB sites (14). The reported euphoric effect of GHB and α β δ α β NEUROSCIENCE subunits and preferably activated 4 1 (EC50 = 140 nM) over 4 its therapeutic effect in narcolepsy cannot be mimicked by bac- δ α (2/3) (EC50 = 8.41/1.03 mM). Introduction of a mutation, 4F71L, in lofen (3) and thus, might involve other targets. Drug discrimina- α4β1(δ)-receptors completely abolished GHB but not GABA func- tion studies also show that rats are able to distinguish between tion, indicating nonidentical binding sites. Radioligand binding GHB and baclofen, further supporting that the effects and 3 studies using the specific GHB radioligand [ H](E,RS)-(6,7,8,9-tetra- mechanisms of the two drugs are different (15). Taken together, hydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid showed these findings strongly suggest that GHB acts at targets in addition a 39% reduction (P = 0.0056) in the number of binding sites in α4 to the GABAB receptor. KO brain tissue compared with WT controls, corroborating the direct Structurally and behaviorally, GHB, in many ways, resembles α fi involvement of the 4-subunit in high-af nity GHB binding. Our its endogenous precursor GABA. Thus, in addition to effects at data link specific GHB forebrain binding sites with α4-containing GABAB receptors, ionotropic GABAA receptors have also been GABAA receptors and postulate a role for extrasynaptic α4δ-contain- studied as possible GHB targets. The role of GABAA receptors ing GABAA receptors in GHB pharmacology and physiology. This in mediating effects of GHB has been controversial, in part be- fi nding will aid in elucidating the molecular mechanisms behind cause of the heterogeneity of this receptor class and the lack of the proposed function of GHB as a neurotransmitter and its unique recombinant functional studies performed; thus, the large number therapeutic effects in narcolepsy and alcoholism. of subtype combinations that can be formed from the numerous known subunits [α(1–6), β(1–3), γ(1–3), δ, ε, θ, π,andρ(1–3)] (16) γ-hydroxybutyric acid receptor | γ-hydroxybutyric acid high-affinity binding have not been investigated. sites | α4-subunit knockout | photoaffinity ligand Depending on composition, GABAA receptors can be found at both synaptic and extrasynaptic locations and mediate phasic γ he GABA metabolite -Hydroxybutyric acid (GHB) is pres- and tonic inhibition, respectively (17). The majority of GABAA Tent in micromolar concentrations in the mammalian brain, receptors contain a γ-subunit, and these receptors can be found where it has been proposed to act as a neurotransmitter (1). Ad- at both synaptic and extrasynaptic locations, whereas the δ-sub- ditionally, GHB is a drug of abuse (Fantasy) and a registered drug unit predominates on peri- and extrasynaptic locations (18, 19), for treating narcolepsy (2) and alcoholism (3). GHB binds to at most commonly accompanied by α(4/6)-subunits. least two distinct populations of low- and high-affinity binding sites In 1987, the work by Snead and Nichols (20) reported evi- in the brain (4). When GHB is ingested in high doses and rea- dence for coupling of the GHB binding site to a GABA-gated ches millimolar concentrations in the brain, it induces behavioral chloride channel; whereas effects of GHB on the major GABAA effects such as sedation, motor incoordination and hypothermia (synaptic) receptors have been refuted (21, 22), effects at (3). These actions are largely mediated by metabotropic GABAB receptors, because effects are prevented by GABAB receptor an- tagonist pretreatment (5) and completely abolished in GABAB(1) Author contributions: N.A., L.F.E., H.B.-O., M.C., and P.W. designed research; N.A., L.F.E., KO mice (6). In addition to the validated GABA receptor effects I.S.V., N.K., T.B., J.V.O., and P.W. performed research; J.V.O., B.F., and R.P.C. contributed B new reagents/analytic tools; N.A., L.F.E., I.S.V., J.V.O., G.M.K., M.C., and P.W. analyzed and other suggested receptors (7), GHB binds with nanomolar to data; and N.A., L.F.E., and P.W. wrote the paper. fi micromolar af nity to a remarkably abundant protein of distinct The authors declare no conflict of interest. spatial distribution and ontogenesis (4), representing an additional This article is a PNAS Direct Submission. functional target. Interestingly, this high-affinity binding protein 1 fi N.A. and L.F.E. contributed equally to this work. is preserved in GABAB(1) KO mice (6) and can be speci cally 2 3 E RS H To whom correspondence may be addressed. E-mail: [email protected] or pw@ probed with [ H]( , )-(6,7,8,9-tetrahydro-5-hydroxy-5 - farma.ku.dk. 3 benzocyclohept-6-ylidene)acetic acid ([ H]NCS-382) (6) and This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. 125 125 [ I]4-hydroxy-4-[4-(2-iodobenzyloxy)phenyl]butanoate ([ I] 1073/pnas.1204376109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1204376109 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 extrasynaptic receptors have, until now, not been systematically and higher was without effect. However, when oocytes were investigated. In fact, several studies infer a role for GHB at injected with the combination of α4-, β(1–3)-, and δ-subunits, extrasynaptic GABAA receptors, such as a correlation between GHB induced inward currents, exhibiting both an intriguing de- elevated GHB levels and increased tonic extrasynaptic inhibition pendence on α4/δ for efficacy and β1 for potency (Table 1). GHB α β δ through GABAA receptors (23). More specifically, effects in- activated 4 1 receptors with high nanomolar potency [EC50 = volved receptor subtypes containing α4- and δ-subunits (24–26). 140 nM (30–660)], inducing a maximum current of 74 ± 10% In this study, we have exploited an in-house–developed, high- relative to GABA (Fig. 2 A and C). At α4β1andα4β1γ2L, 3 mM affinity, and selective GHB photoligand (8, 27, 28) to cross-link GHB elicited a small response (3 ± 0.2%, P =0.01and2± 2%, and partially purify the high-affinity GHB binding protein from P =0.31,Z test compared with control, respectively) (Fig. 2B and α β rat brain cortex, with several GABAA subunits emerging as Table 1). In oocytes injected with RNA for neither 4and 1nor candidate proteins. Functional studies in Xenopus laevis oocytes α4, β1, and δ did we find any indication that GHB could antag- and radioligand binding studies in KO mouse brain tissue veri- onize the GABA response (Fig. S1). Substitution of the β1-subunit fied α4βδ-receptors as high-affinity targets for GHB. Thus, we with β2orβ3 led to a slight reduction in the relative agonist ef- fi – > present direct molecular evidence for a GHB–GABA receptor cacy (53 76%) but a 7,000-fold reduction in potency [EC50 = A – – C interaction in both recombinant and native systems. 8.4 mM (4.0 17) and 1.0 mM (0.6 2.8), respectively] (Fig. 2 ). Construction of a current–voltage (I-V) curve in X. laevis oocytes Results expressing α4β1δ-receptors confirmed that GHB activated a chlo- D α β Proteomics Identify GABA Receptor Subunits as Candidates for High- ride channel (Fig. 2 ). Effects of GHB were undetectable in 4 3-, A α β γ α β γ Affinity GHB Binding Sites. Using an engineered GHB photo- 4 3 2L-, and 4 2 2L-receptors (Table 1).
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