Pharmacology of GABAC receptors: responses to agonists and antagonists distinguish A- and B-subtypes of homomeric ρ receptors expressed in Xenopus oocytes

Pan, Yixin; Khalili, Parham; Ripps, Harris; Qian, Haohua

doi:10.1016/j.neulet.2004.11.024

Cited by 25 publications

(13 citation statements)

References 30 publications

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“…Despite the nonselective nature of amino acids at GABAergic systems, differences in the pharmacology have been reported with glycine, b-alanine and taurine at GABA C subunit composed of perch q-subunits [23]. As a result, it would be interesting to evaluate the guanidino compounds reported here against other GABA C receptor subunits such as the human q2 to determine if there are differences in their activity and thus further contribute to the structure-activity profile of these receptors.…”

Section: Discussionmentioning

confidence: 92%

“…Both taurine [23,24] and homohypotaurine [30], the sulfonic acid and sulfinic acid analogs of glycine, respectively, have been shown to be agonists at GABA C receptors. In contrast, the guanidino analog of homohypotaurine, 2-guanidino-ethanesulfinic acid (4) acted as an antagonist.…”

Section: Discussionmentioning

confidence: 99%

“…Glycine [22][23][24], taurine [23,24] and b-alanine [22,23] have been shown to activate GABA C receptors at concentrations that may be reached in the synapse indicating that, like GABA, these amino acids can modulate synaptic transmission across GABAergic synapses. The activities of these three amino acids are weak, activating the receptors at millimolar concentrations.…”

Section: Introductionmentioning

confidence: 99%

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Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

et al. 2009

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GABA(C) receptors play a role in myopia, memory-related disorders and circadian rhythms signifying a need to develop potent and selective agents for this class of receptors. Guanidino analogs related to glycine, beta-alanine and taurine were evaluated at human rho(1)GABA(C) receptors expressed in Xenopus oocytes using 2-electrode voltage clamp methods. Of the 12 analogs tested, 8 analogs were active as antagonists and the remaining were inactive. (S)-2-guanidinopropionic acid (IC(50) = 2.2 microM) and guanidinoacetic acid (IC(50) = 5.4 microM; K (B) = 7.75 microM [pK (B) = 5.11 +/- 0.06]) were the most potent being competitive antagonists at this receptor. In contrast, the beta-alanine and GABA guanidino analogs showed reduced activity, indicating the distance between the carboxyl carbon and terminal nitrogen of the guanidino group is critical for activity. Substituting the C2-position of guanidinoacetic acid with various alkyl groups reduced activity indicating that steric effects may impact on activity. The results of this study contribute to the structure-activity-relationship profile required in developing novel therapeutic agents.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

et al. 2009

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“…TPMPA-insensitivity observed here contradicts most reports within the literature. However, TPMPA-insensitivity has been observed in expression systems (Pan et al, 2005) and suggests possible GABA receptor subunit composition in zebrafish. The different ρ subunits (i.e., ρ1A, ρ1B, ρ2A, and ρ2B) display differential sensitivities to TPMPA: A-type receptors are highly sensitive to TPMPA; B-type receptors are less sensitive (Pan et al, 2005).…”

Section: Differential Antagonist Sensitivities May Reflect Differencementioning

confidence: 99%

“…However, TPMPA-insensitivity has been observed in expression systems (Pan et al, 2005) and suggests possible GABA receptor subunit composition in zebrafish. The different ρ subunits (i.e., ρ1A, ρ1B, ρ2A, and ρ2B) display differential sensitivities to TPMPA: A-type receptors are highly sensitive to TPMPA; B-type receptors are less sensitive (Pan et al, 2005). As the GABA responses in most isolated bipolar cells were insensitive to TPMPA, these receptors are probably assembled from ρ1B and/or ρ2B subunits.…”

Section: Differential Antagonist Sensitivities May Reflect Differencementioning

confidence: 99%

Electrophysiological evidence of GABA_A and GABA_C receptors on zebrafish retinal bipolar cells

2008

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To refine inhibitory circuitry models for ON and OFF pathways in zebrafish retina, GABAergic properties of zebrafish bipolar cells were studied with two techniques: whole cell patch responses to GABA puffs in retinal slice, and voltage probe responses in isolated cells. Retinal slices documented predominantly axon terminal responses; isolated cells revealed mainly soma-dendritic responses. In the slice, GABA elicited a conductance increase, GABA responses were more robust at axon terminals than dendrites, and E rev varied with [Cl − ] in . Axon terminals of ON-and OFFtype cells were similarly sensitive to GABA (30-40pA peak current); axotomized cells were unresponsive. Bicuculline-sensitive, picrotoxin-sensitive, and picrotoxin-insensitive components were identified. Muscimol was as effective as GABA; baclofen was ineffective. Isolated bipolar cells were either intact or axotomized. Even in cells without an axon, GABA or muscimol (but not baclofen) hyperpolarized dendritic and somatic regions, suggesting significant distal expression. Median fluorescence change for GABA was −0.22 log units (~−16mV); median half-amplitude dose was 0.4μM. Reduced [Cl − ] out blocked GABA responses. GABA hyperpolarized isolated ONbipolar cells, OFF-cells were either unresponsive or depolarized. Hyperpolarizing GABA responses in isolated cells were bicuculline and TPMPA insensitive, but blocked or partially blocked by picrotoxin or zinc. In summary, axon terminals contain bicuculline-sensitive GABA A

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Tests for Anxiolytic Activity

Kallman¹

2016

Drug Discovery and Evaluation: Pharmacological Assays

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Pharmacology of GABAC receptors: responses to agonists and antagonists distinguish A- and B-subtypes of homomeric ρ receptors expressed in Xenopus oocytes

Cited by 25 publications

References 30 publications

Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

Electrophysiological evidence of GABA_A and GABA_C receptors on zebrafish retinal bipolar cells

Tests for Anxiolytic Activity

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Pharmacology of GABAC receptors: responses to agonists and antagonists distinguish A- and B-subtypes of homomeric ρ receptors expressed in Xenopus oocytes

Cited by 25 publications

References 30 publications

Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

Electrophysiological evidence of GABAA and GABAC receptors on zebrafish retinal bipolar cells

Tests for Anxiolytic Activity

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Electrophysiological evidence of GABA_A and GABA_C receptors on zebrafish retinal bipolar cells