Molecular Conformation of GABA

Steward, E. G.; Player, R. B.; Quilliam, J. P.; Brown, David A.; Pringle, Michael J.

doi:10.1038/newbio233087a0

Cited by 33 publications

(8 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The optimum configuration for activation of ganglionic GABAreceptors corresponds with that previously deduced for central receptors in terms of the maximum distance between the N-C-0-charge centres (see Kier & Truitt, 1970;Beart et aL, 1971). The latter were derived from consideration of the activity of rigid GABA-analogues: this 20 MM) implied that GABA normally interacts with the receptors in a fully-extended configuration, in spite of an apparent tendency toward partial folding in crystalline form (Steward, Player, Quilliam, Brown & Pringle, 1971). The symmetrical potency-chain length graph in Fig.…”

Section: Discussionmentioning

confidence: 99%

DEPOLARIZING ACTIONS OF γ‐AMINOBUTYRIC ACID AND RELATED COMPOUNDS ON RAT SUPERIOR CERVICAL GANGLIA IN VITRO

Bowery

Brown

1974

British J Pharmacology

241

View full text Add to dashboard Cite

1Potential changes in rat superior cervical ganglia were recorded in vitro with surface electrodes.2 y-aminobutyric acid (GABA) produced a transient, low-amplitude ganglion depolarization at rest, and a transient hyperpolarization in ganglia depolarized by carbachol. Depolarization was not prevented by preganglionic denervation. The log dose-response curve for depolarization was sigmoid with a mean ED50 of 12.5 ,iM.3 The ganglion was depolarized in similar manner by the following compounds (mean molar potencies relative to GABA (= 1) in brackets): 3-aminopropane sulphonic acid (3.4), 'y-amino-f3-hydroxybutyric acid (0.27), ,B-guanidino-propionic acid (0.12), guanidinoacetic acid (0.057), 6-aminovaleric acid (0.048),,-alanine (0.01), 2,4-diaminobutyric acid, 'y-guanidinobutyric acid, taurine and N-methyl-GABA (all <0.01). The folfowing compounds did not depolarize the ganglion at 10 mM concentrations: ai-and ,B-amino-n-butyric acids, a-amino-isobutyric acid, glycine and glutamic acid. 4 Depolarization declined in the continued presence of GABA. Ganglia thus 'desensitized' to GABA showed a diminished response to other amino acids but not to carbachol. 5 The effect of GABA was not antagonized by hyoscine and hexamethonium in combination, in concentrations sufficient to block responses to carbachol. 6 Responses to GABA were blocked more readily than those to carbachol by bicuculline (IC50, 14 gM) and picrotoxin (IC50, 37 gM). Strychnine (IC50, 73 ,M) was a relatively weak and less selective GABA-antagonist. 7 It is concluded that sympathetic ganglion cells possess receptors for GABA and related amino acids which are (a) different from the acetylcholine receptors and (b) similar to GABA receptors in the central nervous system.

show abstract

Section: Discussionmentioning

confidence: 99%

DEPOLARIZING ACTIONS OF γ‐AMINOBUTYRIC ACID AND RELATED COMPOUNDS ON RAT SUPERIOR CERVICAL GANGLIA IN VITRO

Bowery

Brown

1974

British J Pharmacology

241

View full text Add to dashboard Cite

show abstract

“…Recent studies by Beart, Curtis & Johnston (1971) using a conformationally-restricted analogue, 4-aminotetrolic acid, also suggest that the extended form of GABA is the physiologically active conformation. However, studies of the GABA molecule in solid state crystals indicate a spatial separation within the range of 2.7 to 3.1 A (Steward et al, 1971). Van Gelder (1971), on the basis of theoretical calculations, has suggested that the active conformation is a folded form of the molecule.…”

Section: Introductionmentioning

confidence: 99%

“…GABA in aqueous solution can exist in numerous molecular conformations, and the spatial separation of amino and carboxy groups can range from 2.4 to 4.8 A (McGeer, McGeer & McLennan, 1961;Steward, Player, Quilliam, Brown & Pringle, 1971; Van Gelder, 1971;Gilardi, 1973). A previous study using analogues of GABA to characterize the conformation of GABA which is physiologically active on the inhibitory stretch receptor of the crayfish suggests that the optimal spatial separation of the amino and carboxy groups is 4.0 A or more (McGeer et al, 1961), a separation most consistent with an extended conformation of GABA.…”

Section: Introductionmentioning

confidence: 99%

Characterization of an Inhibitory Receptor in Rat Hippocampus: A Microiontophoretic Study Using Con‐formationally Restricted Amino Acid Analogues

Segal

Sims

Smissman

1975

British J Pharmacology

View full text Add to dashboard Cite

I Pyramidal cells in rat hippocampus were used to study the molecular dimensions of a receptor for inhibitory amino acids in the central nervous system. The inhibitory potencies of y-aminobutyrate (GABA), ,B-alanine and glycine were compared by standard microiontophoretic techniques. Subsequently, rigid cyclopentane and cyclohexane amino acid analogues were applied by iontophoresis and their relative efficacies were compared with those of the naturally occurring amino acids. 2 GABA was the most effective of the small aliphatic amino acids in producing inhibition of the firing of hippocampal pyramidal neurones. 13-Alanine was less effective and glycine was the least effective. GABA-induced inhibition was antagonized by concurrent iontophoresis of picrotoxin or bicuculline, whereas strychnine did not antagonize GABA inhibition. 3 The ability of the series of substituted aminocyclopentane and aminocyclohexane carboxylic acids to produce inhibition of pyramidal cells was a direct function of the separation of amino and carboxylic acid groups. In both series of the cyclic amino acids the most potent inhibition was demonstrated when the spatial separation was similar to that of the extended GABA molecule (4.74 A). Additionally, the inhibition of hippocampal pyramidal cells by (±)-cis-3-amino-cyclopentanecarboxylic acid, like that produced by GABA, could be blocked by simultaneous application of picrotoxin or bicuculline, but not by strychnine. 4 The present results suggest that the physiologically active conformation of GABA is the fully extended molecule, and additionally indicate that one dimension of the postsynaptic receptor site is within the range of 4.2 to 4.8 angstr6ms.

show abstract

“…The interest in this work lies in the accurate determination of molecular conformations of these compounds which might assist in a better understanding of their biological action. Structureactivity correlations of bicuculline with other related compounds of known structure will be necessary so that detailed models may be better interpreted, as at present they have, of necessity, been speculative (Steward et al, 1971).…”

Section: Introductionmentioning

confidence: 99%

Crystal and molecular structure of bicuculline

Gorinsky

Moss

1973

Journal of Crystal and Molecular Structure

View full text Add to dashboard Cite

The crystal and molecular structure of the phthalide isoquinoline alkaloid bicuculline, C20H17NO6, has been determined by X-ray diffraction methods. The compound crystallizes in the orthorhombic space group P21212~ (No. 19) with a = 14.49, b = 10.90 and c = 10'43 A. The atomic parameters were refined by least squares to give a conventional R-factor of 0.0437 for 1557 symmetry independent reflections.

show abstract

Molecular Conformation of GABA

Cited by 33 publications

References 7 publications

DEPOLARIZING ACTIONS OF γ‐AMINOBUTYRIC ACID AND RELATED COMPOUNDS ON RAT SUPERIOR CERVICAL GANGLIA IN VITRO

DEPOLARIZING ACTIONS OF γ‐AMINOBUTYRIC ACID AND RELATED COMPOUNDS ON RAT SUPERIOR CERVICAL GANGLIA IN VITRO

Characterization of an Inhibitory Receptor in Rat Hippocampus: A Microiontophoretic Study Using Con‐formationally Restricted Amino Acid Analogues

Crystal and molecular structure of bicuculline

Contact Info

Product

Resources

About