Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Physiol Rep
2017 Mar 01;56:. doi: 10.14814/phy2.13129.
Show Gene links
Show Anatomy links
GABAB receptor attenuation of GABAA currents in neurons of the mammalian central nervous system.
Shen W
,
Nan C
,
Nelson PT
,
Ripps H
,
Slaughter MM
.
???displayArticle.abstract???
Ionotropic receptors are tightly regulated by second messenger systems and are often present along with their metabotropic counterparts on a neuron's plasma membrane. This leads to the hypothesis that the two receptor subtypes can interact, and indeed this has been observed in excitatory glutamate and inhibitory GABA receptors. In both systems the metabotropic pathway augments the ionotropic receptor response. However, we have found that the metabotropic GABAB receptor can suppress the ionotropic GABAA receptor current, in both the in vitro mouse retina and in human amygdala membrane fractions. Expression of amygdala membrane microdomains in Xenopus oocytes by microtransplantation produced functional ionotropic and metabotropic GABA receptors. Most GABAA receptors had properties of α-subunit containing receptors, with ~5% having ρ-subunit properties. Only GABAA receptors with α-subunit-like properties were regulated by GABAB receptors. In mouse retinal ganglion cells, where only α-subunit-containing GABAA receptors are expressed, GABAB receptors suppressed GABAA receptor currents. This suppression was blocked by GABAB receptor antagonists, G-protein inhibitors, and GABAB receptor antibodies. Based on the kinetic differences between metabotropic and ionotropic receptors, their interaction would suppress repeated, rapid GABAergic inhibition.
Figure 1.
GABA‐ and muscimol‐sensitive responses from the Xenopus oocytes transplanted with native human amygdala membrane fraction. Sample voltage‐clamp recordings from Xenopus oocytes microtransplanted with human amygdala plasma membrane in response to various concentrations of GABA (A) or muscimol (B). (C) Average dose–response curves of GABA and muscimol. (D) Example of currents evoked by 50 μmol/L GABA at various holding voltages (mV): −70, −50, −30, −10, and 10. (E) Current–voltage relationship of GABA in the transplanted oocytes (n = 4). (F) GABA current in the sham‐injected oocytes.
Figure 2. Pharmacology of GABAA receptors from transplanted human amygdala. (A, B) Examples of dose‐dependent inhibition of GABA currents by SR95531 and bicuculline. (C) Dose‐dependent inhibition curves of SR95531, bicuculline, and picrotoxin (PTX) against 50 μmol/L GABA. (D) Histogram shows normalized average GABA currents alone and in the presence of PTX, bicuculline, or SR95531, as well as current produced by CACA (cis‐aminocrotonic acid). Statistically there was no difference between the CACA currents and the currents insensitive to picrotoxin, bicuculline, or SR95531 (*, **, *** indicate P < 0.05, Student's t‐test). (E) A small TPMPA‐sensitive GABA current observed when α‐subunit GABAA receptors were blocked by bicuculline. (F) CACA‐sensitive currents were partially blocked by TPMPA. (G) Small GABA current in the presence of picrotoxin.
Figure 3. Activation of GABABR inhibits α‐subunit GABAAR currents. (A) 10 μmol/L and 100 μmol/L baclofen inhibit muscimol (10 μmol/L)‐evoked currents. (B) The suppressive effect of baclofen was blocked by 20 μmol/L CGP52432, a GABABR inhibitor; note that the baclofen with and without CGP52432 have no effect on the resting membrane current (see asterisk). (C) Baclofen (10 μmol/L) did not suppress the CACA‐activated current. (D) Summary of the effects of 10 μmol/L baclofen on the currents produced by muscimol or CACA. On average, 10 μmol/L baclofen (BAC) reduced 48 ± 3% (n = 12) of 10 μmol/L muscimol‐generated peak current, but had insignificant effects on 100 μmol/L CACA‐generated currents. (E) Western blotting indicates that anti‐GBR2 antibody detected a single protein band at 107 kDa from a sample of the membrane fraction (left), and the anti‐GBR2 detection of GABABRs on the membrane surface of oocytes injected with either the membrane fraction or sham control. The inserts show magnified views of oocyte membrane. (F, G) Baclofen (10 μmol/L) had small effects on the oocytes injected with the anti‐GBR2 applied membrane fractions. (H) Internal perfusion of GDP‐βS blocked 10 μmol/L baclofen‐produced inhibition.
Figure 4. The GABA‐elicited currents were increased when blocking GABAB receptors (A). Both CGP55845 and CGP52432, selective GABAB antagonists, increase GABA (50 μmol/L) currents in transplanted oocytes. (B) The mean percentage increase of GABA current by CGP55845 or CGP52432. In contrast, CGP52432 has no effect on 10 μmol/L muscimol‐elicited currents (C).
Figure 5. Activation of GABABRs suppressed GABAAR currents in mouse retinal ganglion cells. (A) Example of the current–voltage relationship of ganglion cells in whole‐cell recording. (B) Baclofen suppressed muscimol‐elicited currents in a ganglion cell clamped at various voltages. (C) Average current–voltage relationship of muscimol‐elicited currents with and without baclofen. (D) The effects of baclofen were blocked by intracellular application of GDP‐β‐S (100 μmol/L).
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998, Pubmed
Barnard,
International Union of Pharmacology. XV. Subtypes of gamma-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function.
1998,
Pubmed
Bettler,
Molecular structure and physiological functions of GABA(B) receptors.
2004,
Pubmed
Bowery,
(-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor.
1980,
Pubmed
Chalifoux,
GABAB receptor modulation of synaptic function.
2011,
Pubmed
Chen,
Presynaptic GABAB autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons.
1998,
Pubmed
Connelly,
GABAB Receptors Regulate Extrasynaptic GABAA Receptors.
2013,
Pubmed
Cunha,
GABA(C) Receptors in the Lateral Amygdala: A Possible Novel Target for the Treatment of Fear and Anxiety Disorders?
2010,
Pubmed
Deisz,
Frequency-dependent depression of inhibition in guinea-pig neocortex in vitro by GABAB receptor feed-back on GABA release.
1989,
Pubmed
Delaney,
Pathway-specific targeting of GABA(A) receptor subtypes to somatic and dendritic synapses in the central amygdala.
2001,
Pubmed
Dutar,
Pre- and postsynaptic GABAB receptors in the hippocampus have different pharmacological properties.
1988,
Pubmed
Eusebi,
Microtransplantation of ligand-gated receptor-channels from fresh or frozen nervous tissue into Xenopus oocytes: a potent tool for expanding functional information.
2009,
Pubmed
,
Xenbase
Feng,
Serotonin receptors modulate GABA(A) receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons.
2001,
Pubmed
Flores-Gracia,
GABA(A) ρ receptor mechanisms in the rat amygdala and its role in the modulation of fear and anxiety.
2010,
Pubmed
Fried,
Directional selectivity is formed at multiple levels by laterally offset inhibition in the rabbit retina.
2005,
Pubmed
Friedman,
Evidence for functionally distinct subclasses of gamma-aminobutyric acid receptors in rabbit retina.
1990,
Pubmed
Garaycochea,
GABAB receptors enhance excitatory responses in isolated rat retinal ganglion cells.
2016,
Pubmed
Geng,
Structural mechanism of ligand activation in human GABA(B) receptor.
2013,
Pubmed
Hüttmann,
Molecular and functional properties of neurons in the human lateral amygdala.
2006,
Pubmed
Johnston,
GABAc receptors: relatively simple transmitter -gated ion channels?
1996,
Pubmed
Kamatchi,
Functional coupling of presynaptic GABAB receptors with voltage-gated Ca2+ channel: regulation by protein kinases A and C in cultured spinal cord neurons.
1990,
Pubmed
Karlsson,
Blockade of GABAB receptors accelerates amygdala kindling development.
1992,
Pubmed
Kaupmann,
Human gamma-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K+ channels.
1998,
Pubmed
Kellenberger,
Function of the alpha 1 beta 2 gamma 2S gamma-aminobutyric acid type A receptor is modulated by protein kinase C via multiple phosphorylation sites.
1992,
Pubmed
,
Xenbase
Knight,
The pharmacology of adenylyl cyclase modulation by GABAB receptors in rat brain slices.
1996,
Pubmed
Kobayashi,
Kinetics of GABAB autoreceptor-mediated suppression of GABA release in rat insular cortex.
2012,
Pubmed
Koulen,
Presynaptic and postsynaptic localization of GABA(B) receptors in neurons of the rat retina.
1998,
Pubmed
Krishek,
Regulation of GABAA receptor function by protein kinase C phosphorylation.
1994,
Pubmed
,
Xenbase
Kubota,
GABAB receptor transduction mechanisms, and cross-talk between protein kinases A and C, in GABAergic terminals synapsing onto neurons of the rat nucleus basalis of Meynert.
2003,
Pubmed
Kusano,
Cholinergic and catecholaminergic receptors in the Xenopus oocyte membrane.
1982,
Pubmed
,
Xenbase
Lang,
Synaptic responsiveness of interneurons of the cat lateral amygdaloid nucleus.
1998,
Pubmed
Lehner,
Differences in the density of GABA-A receptor alpha-2 subunits and gephyrin in brain structures of rats selected for low and high anxiety in basal and fear-stimulated conditions, in a model of contextual fear conditioning.
2010,
Pubmed
Li,
GABAA and GABAB receptors differentially regulate synaptic transmission in the auditory thalamo-amygdala pathway: an in vivo microiontophoretic study and a model.
1996,
Pubmed
Liu,
Chronic stress impairs GABAergic control of amygdala through suppressing the tonic GABAA receptor currents.
2014,
Pubmed
McDonald,
Adjacent phosphorylation sites on GABAA receptor beta subunits determine regulation by cAMP-dependent protein kinase.
1998,
Pubmed
Miledi,
Microtransplantation of functional receptors and channels from the Alzheimer's brain to frog oocytes.
2004,
Pubmed
,
Xenbase
Miledi,
Microtransplantation of neurotransmitter receptors from cells to Xenopus oocyte membranes: new procedure for ion channel studies.
2006,
Pubmed
,
Xenbase
Miledi,
Expression of functional neurotransmitter receptors in Xenopus oocytes after injection of human brain membranes.
2002,
Pubmed
,
Xenbase
Pan,
Selective gating of glutamatergic inputs to excitatory neurons of amygdala by presynaptic GABAb receptor.
2009,
Pubmed
Quirk,
Inhibition of the amygdala: key to pathological states?
2003,
Pubmed
Rainnie,
Inhibitory transmission in the basolateral amygdala.
1991,
Pubmed
Schmitt,
University of Kentucky Sanders-Brown healthy brain aging volunteers: donor characteristics, procedures and neuropathology.
2012,
Pubmed
Shen,
Metabotropic GABA receptors facilitate L-type and inhibit N-type calcium channels in single salamander retinal neurons.
1999,
Pubmed
Shen,
GABAB receptor attenuation of GABAA currents in neurons of the mammalian central nervous system.
2017,
Pubmed
,
Xenbase
Song,
GABA(B) receptor feedback regulation of bipolar cell transmitter release.
2010,
Pubmed
Song,
Protein kinase C regulation of GABAA receptors.
2005,
Pubmed
Taniyama,
Activation of protein kinase C suppresses the gamma-aminobutyric acidB receptor-mediated inhibition of the vesicular release of noradrenaline and acetylcholine.
1992,
Pubmed
Tao,
Postsynaptic GABAB receptors enhance extrasynaptic GABAA receptor function in dentate gyrus granule cells.
2013,
Pubmed
Wisden,
The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon.
1992,
Pubmed
Xi,
Baclofen reduces GABAA receptor responses in acutely dissociated neurons of bullfrog dorsal root ganglia.
1997,
Pubmed
Yamada,
GABA(B) receptor-mediated presynaptic inhibition of glutamatergic and GABAergic transmission in the basolateral amygdala.
1999,
Pubmed
Zhang,
Cloning of a gamma-aminobutyric acid type C receptor subunit in rat retina with a methionine residue critical for picrotoxinin channel block.
1995,
Pubmed
,
Xenbase
