Investigating the Role of Loop C Hydrophilic Residue ‘T244’ in the Binding Site of ρ1 GABAC Receptors via Site Mutation and Partial Agonism

Naffaa, Moawiah M.; Absalom, Nathan L.; Solomon, V. Raja; Chebib, Mary; Hibbs, David E.; Hanrahan, Jane R.

doi:10.1371/journal.pone.0156618

Cited by 7 publications

(8 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is made up of 20 residues that are directly or indirectly involved in GABA binding 30 ; two of these residues, located in one of each subunit (Y198 in the + subunit and S168 in the − subunit), are involved in the recognition of the amine group of GABA. The acidic group of GABA is bound to R104 31 and T244 32 (in the − and + subunit, respectively) (Fig. 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…Previous reports showed that residues T224 and R104 are critical for interacting with the acidic moiety of GABA and channel gating. Mutations in R104 induce a reconfiguration of the GABA binding site unable to gate the channel 32 , whereas mutation T224A reduces the efficacy of GABA 33 . In our docking model, DOPAC is less than 5 Å from T224 and R104, but the larger distance to Y198 and S168 (more than 7 Å) would make the hydrogen bonds unstable.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Antagonistic effect of dopamine structural analogues on human GABAρ1 receptor

Alaniz-Palacios

Martı́nez-Torres

2017

Sci Rep

View full text Add to dashboard Cite

GABAergic and dopaminergic pathways are co-localized in several areas of the central nervous system and recently several reports have shown co-release of both neurotransmitters. The GABA-A receptor (β and ρ1 subunits) is modulated by dopamine (DA) and, interestingly, GABAρ1 can be modulated by several biogenic amines. Here we explored the effects of the metabolites of the dopaminergic pathway and other structural analogues of DA on GABAρ1 and the DA gated ion channel (LGC-53) from Caenorhabditis elegans expressed in Xenopus laevis oocytes. Our findings show an antagonistic effect of the metabolite 3-Methoxytyramine (3-MT, IC50 = 285 ± 30 µM) with similar potency compared to DA on induced GABA currents; however, it was inactive on LGC-53. The structural DA analogues and metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 2-phenylethylamine (β-PEA) and 4-amino-1-butanol (4-AM-1-OH), antagonized GABAρ1 currents, whereas β-PEA acted as partial agonists on LGC-53, indicating that the putative binding sites of both receptors may share structural characteristics. These results suggest that the DA metabolites 3-MT, DOPAC and HVA modulate GABAρ1 and possibly affect the activity of the receptors that include this subunit in vivo.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Antagonistic effect of dopamine structural analogues on human GABAρ1 receptor

Alaniz-Palacios

Martı́nez-Torres

2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…A range of agonists studied at the T244S mutant receptor demonstrated many‐fold decreases in potency, while antagonist activity remained unaffected by the mutation (Yamamoto et al, ). Thr 244 is proposed to be essential for the formation of an H‐bond with agonists initiating conformational changes through movement of Loop C to open the channel (Naffaa et al, ).…”

Section: Gaba‐ρ1 Agonist Binding Sitementioning

confidence: 99%

GABA‐ρ receptors: distinctive functions and molecular pharmacology

Naffaa

Hung

Chebib

et al. 2017

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

The homomeric GABA-ρ ligand-gated ion channels (also known as GABA or GABA -ρ receptors) are similar to heteromeric GABA receptors in structure, function and mechanism of action. However, their distinctive pharmacological properties and distribution make them of special interest. This review focuses on GABA-ρ ion channel structure, ligand selectivity toward ρ receptors over heteromeric GABA receptor sub-types and selectivity between different homomeric ρ sub-type receptors. Several GABA analogues show selectivity at homomeric GABA-ρ receptors over heteromeric GABA receptors. More recently, some synthetic ligands have been found to show selectivity at receptors formed from one ρ subtype over others. The unique pharmacological profiles of these agents are discussed in this review. The classical binding site of GABA within the orthosteric site of GABA-ρ homomeric receptors is discussed in detail regarding the loops and residues that constitute the binding site. The ligand-residue interactions in this classical binding and those of mutant receptors are discussed. The structure and conformations of GABA are discussed in regard to its flexibility and molecular properties. Although the binding mode of GABA is difficult to predict, several interactions between GABA and the receptor assist in predicting its potential conformation and mode of action. The structure-activity relationships of GABA and structurally key ligands at ρ receptors are described and discussed.

show abstract

“…We subsequently implemented two-electrode voltage-clamp electrophysiology (TEVC) to record the pharmacological effect of the ligands in this study at GABA-2 receptors expressed on the membrane of Xenopus oocytes. The GABA analogues used in this work were chosen because they have previously shown interesting pharmacological profiles at GABA-1 WT (wild type) and mutant receptors [19,20].…”

Section: Introductionmentioning

confidence: 99%

“…Models of GABA-bound GABA-2 were built based on the GABA-1 model in an open conformation using Prime 3.2 software [24]. These generated models were reviewed and verified as described in our previous published work [19].…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Effect of GABA Analogues on GABA-ϱ2 Receptors and Their Subtype Selectivity

Naffaa

Hibbs

Chebib

et al. 2022

Life

Self Cite

View full text Add to dashboard Cite

GABAϱ receptors are distinctive GABAergic receptors from other ionotropic GABAA and metabotropic GABAB receptors in their pharmacological, biochemical, and electrophysiological properties. Although GABA-ϱ1 receptors are the most studied in this subfamily, GABA-ϱ2 receptors are widely distributed in the brain and are considered a potential target for treating neurological disorders such as stroke. The structure of GABA-ϱ2 receptors and their pharmacological features are poorly studied. We generated the first homology model of GABA-ϱ2 channel, which predicts similar major interactions of GABA with the binding-site residues in GABA-ϱ1 and GABA-ϱ2 channels. We also investigated the pharmacological properties of several GABA analogues on the activity of GABA-ϱ2 receptors. In comparison to their pharmacological effect on GABA-ϱ1 receptors, the activation effect of these ligands and their potentiation/inhibition impact on GABA response have interestingly shown inter-selectivity between the two GABA-ϱ receptors. Our results suggest that several GABA analogues can be used as research tools to study the distinctive physiology of GABA-ϱ1 and GABA-ϱ2 receptors. Furthermore, their partial agonist effect may hold promise for the future discovery of selective modulatory agents on GABAA receptors.

show abstract

Investigating the Role of Loop C Hydrophilic Residue ‘T244’ in the Binding Site of ρ1 GABAC Receptors via Site Mutation and Partial Agonism

Cited by 7 publications

References 36 publications

Antagonistic effect of dopamine structural analogues on human GABAρ1 receptor

Antagonistic effect of dopamine structural analogues on human GABAρ1 receptor

GABA‐ρ receptors: distinctive functions and molecular pharmacology

Pharmacological Effect of GABA Analogues on GABA-ϱ2 Receptors and Their Subtype Selectivity

Contact Info

Product

Resources

About