Article Figures & Data
Figures
- Figure 1
Structures of high-affinity GABABreceptor agonists.
- Figure 2
Structures of low-affinity GABABreceptor antagonists.
- Figure 3
Structures of high-affinity GABABreceptor antagonists.
- Figure 4
Structures of high-affinity125I-labeled GABAB receptor antagonist.
Tables
Structural information 7TM heterodimer formed by combination of two subunits Subunit 1, h 961aa, AJ012185 Subunit 1, r 960aa, Y10369 Subunit 2, h 941aa, AJ012188 Subunit 2, r 941aa, AJ011318 Functional assays Inhibition of forskolin-stimulated cAMP formation in rat cerebral cortex slices1-a 1-b Inhibition of twitch responses in rat isolated anoccocygeus muscle1-c Neuronal hyperpolarization in rat hippocampal slice1-d Inhibition of depolarization-evoked neurotransmitter release from CNS synaptosomes1-e Effect on [35 S]GTPγS-binding in native receptor and recombinant receptor preparations1-f Agonists selective: (−)-baclofen, 3APPA, 3APMPA, CGP445321-g non-selective: GABA1-h Agonist potencies (−)baclofen (IC50 = 30 nM), 3APPA (5 nM), 3APMPA (16 nM), GABA (20 nM), CGP44532 (45 nM)1-i Antagonists selective: CGP35348, CGP36742, CGP55845A, CGP62349, SCH50911, phaclofen1-j Antagonist potencies CGP35348 (IC50 = 35 μM), CGP36742 (35 μM), CGP55845A (2 nM), CGP62349 (0.5 nM), SCH50911 (11 μM)1-i 1-k Radioligand assays Rat brain synaptic membranes1-l CHO cell line expressing human GABAB(1) and GABAB(2) 1-m Radioligands [3H]GABA,1-l[3H](−)-baclofen,1-n[3H]CGP54626,1-o[3H]CGP62349,1-p[125I]CGP64213,1-k[125I]CGP718721-k Transduction Inhibition of adenylate cyclase1-h mechanisms Inhibition of membrane Ca2+conductance1-h Increased K+conductance via Gi/Goproteins1-h Stimulation of MAP kinase1-q Receptor distribution Pre- and postsynaptic locations on neurones of mammalian CNS and terminals of peripheral autonomic nerve fibers and sensory fibers; rat thalamic nuclei, cerebellar molecular layer, cerebral cortex, interpeduncular nucleus, superior colliculus, dorsal horn of spinal cord1-r 1-s Tissue functions Auto- and heteroreceptor-mediated inhibition of transmitter release Slow inhibitory postsynaptic potentials1-h Phenotypes −GABA1knockout1-t 1-u Loss of pre- and postsynaptic receptor function in hippocampus Lack of GABAB-binding sites throughout brain Loss of GABAB-stimulated GTPγS binding (whole brain) Survival −27 days,1-t >140 days1-u Spontaneous epileptiform seizures Hyperalgesic Hyperlocomotive Impaired learning in passive avoidance paradigm No evidence for receptor subtyping obtained Modified with permission from the IUPHAR Compendium of Receptor Characterization and Classification (2000) IUPHAR Media, London.
CNS, central nervous system; [35 S]GTPγS, guanosine 5′-O-(3−[35S] thio)triphosphate; MAP, mitogen-activated protein; 7TM, seven-transmembrane.
↵1-a Xu and Wojcik, 1986.
↵1-b Hill, 1985.
↵1-c Muhyaddin et al., 1982.
↵1-d Newberry and Nicoll, 1984.
↵1-e Gemignani et al., 1994.
↵1-f Watson et al., 1996.
↵1-g Froestl et al., 1995a.
↵1-h Bowery, 1993.
↵1-i Froestl and Mickel, 1997.
↵1-j Froestl et al., 1995b.
↵1-k Kaupmann et al., 1997.
↵1-l Bowery et al., 1983.
↵1-m Hirst et al., 2000.
↵1-n Bowery et al., 1985.
↵1-o Bittiger et al., 1992.
↵1-p Bittiger et al., 1996a.
↵1-q Schulz and Hollt, 1998.
↵1-r Bowery et al., 1987.
↵1-s Chu et al., 1990.
↵1-t Prosser et al., 2001.
↵1-u Schuler et al., 2001.
- Table 2
GABABreceptor subtypes IC50values of antagonists (μM). The drugs were tested against (−)-baclofen.
Drug Neurotransmitter Released GABA GLU SRIF CCK Rat cortex Phaclofen 79.2 >300 62.6 66.1 CGP35348 >300 4.2 3.6 3.5 CGP52432 0.08 9.3 3.4 0.11 CGP47656 3.1 (Ago) Ago >300 CGP36742 >100 >100 0.14 >100 Human cortex Phaclofen ≈100 >300 N.D. N.D. CGP35348 >100 ≈10 24.4 13.9 CGP52432 ≪1 >1; < 30 0.06 0.08 CGP47656 <10 N.D. Ago Ago CGP36742 >100 >100 ≈5 >100 GLU, glutamate; SRIF, somatotropin release-inhibiting factor; Ago, against; (Ago) partial agonist; CCK, cholecystokinin; N.D., not determined.
In this issue
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- Article
- Abstract
- I. Introduction
- II. γ-Aminobutyric AcidB Receptor Structure
- III. γ-Aminobutyric AcidB Receptor Effector Mechanisms
- IV. γ-Aminobutyric AcidB Receptor Subtypes
- V. γ-Aminobutyric AcidB Receptor Distribution
- VI. γ-Aminobutyric AcidB Receptor-Mediated Responses
- VII. Conclusions
- Footnotes
- Abbreviations
- References
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