GABAa receptors how subunit combinations affect synaptic and extrasynaptic transmission

Many factors will influence the type of IPSCs mediated by GABAA receptors the number of GABAA receptors at the synapse the subunit composition of the receptors which influences the kinetics the phosphorylation state of the receptor a differential modulation of synaptic and non-synaptic receptors the Cl reversal potential the GABA transient in the synaptic cleft and regulation by neuromodulators (Mody and Pearce, 2004). A typical synaptic pulse of GABA is often cited as 0.3-1.0 mM lasting less...

GABA concentration changes at the synapse

GABA is synthesized in the cytosol and accumulated into synaptic vesicles by a vesicular transporter (VGAT VIAAT (McIntire et al., 1997 Chaudhry et al., 1998 Wojcik et al., 2006)) that is able to generate an intra-lumenal concentration thought to be in the range of several hundred milli-molar (Axmacher et al., 2004). Thus, the fusion of a single vesicle liberates many thousands of GABA molecules into the synaptic cleft ( 20 nm wide and 0.05-0.2 mm2 in area), generating a GABA concentration...

Ionic permeability of GABAa receptors

Irrespective of their subunit composition, all GABAa receptors are permeable to the same ions. Based on measurements of the permeation of a series of large, weakly hydrated probe anions, the diameter of the narrowest part of the GABAA receptor channel has been estimated at about 0.55nm (Inomata et al., 1986 Bormann et al., 1987 Akaike et al., 1989 Fatima-Shad and Barry, 1993 Kaila, 1994 Wotring et al., 1999). However, the GABAA channel is not a simple water-filled pore (Takeuchi and Takeuchi,...

GABAa receptor gating and the IPSC

GABAa receptors undergo considerable spontaneous motion while in the closed state (Bera and Akabas, 2005), suggesting a level of flexibility appropriate for rapid gating (Maconochie et al., 1994 Jones and Westbrook, 1995 McClellan and Twyman, 1999 Burkat et al., 2001 Chakrapani and Auerbach, 2005). In theory, the channel can open in the absence of agonist, albeit with an extremely low probability (Chang and Weiss, 1999a Campo-Soria et al., 2006). Of note, some recombinant (Sigel et al., 1989...

Synaptic GABAa receptors aPy subunit combinations and anchoring role of the y2 subunit and gephyrin

Placing GABAA receptors at synapses requires specific proteins that interact directly or indirectly with the g subunits. For example, targeting some GABAA receptor subtypes to GABAergic terminals involves the widely expressed microtubule-binding protein gephyrin (Ramming et al., 2000). The best studied brain area for this has been the hippocampus, but splice forms of gephyrin are found throughout the basal ganglia (Ramming et al., 2000) and so the principles of GABAA receptor targeting would be...

GABAa receptor agonists antagonists and allosteric modulators

GABAa receptors display a rich pharmacology (Korpi et al., 2002a Sieghart and Sperk, 2002 Rudolph and Moehler, 2006 Whiting, 2006). Generic GABAA receptors are selectively activated by the GABA agonist muscimol and blocked competitively by the GABA antagonists bicuculline and SR95531 (receptors assembled with p subunits are bicuculline- and barbiturate-insensitive, having their own unique pharmacology). Picrotoxin blocks GABAA receptors non-competitively, probably by binding to a site in the...

GABA metabolism

Gaba Shunt Glutamate Tca

In the first report Roberts and Frankel, 1950 describing GABA as an interesting amino acid present in relatively large amounts in the brain it was demonstrated that the biosynthetic pathway consisted of a decarboxylation of l-glutamate catalysed by the enzyme l-glutamate decarboxylase GAD . Subsequent studies led to a detailed characterization and purification of this enzyme Roberts and Simonsen, 1963 Wu et al., 1973 Wu and Roberts, 1974 . Further studies including cloning have revealed the...

Piers C Emson

The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, UK Abstract In the basal ganglia the effects of g-aminobutyrate GABA are mediated by both ionotropic GABAa and metabotropic GABAb receptors. Although the existence and widespread distribution in the CNS of the GABAB receptor had been established in the 1980s the field of GABAB research was revolutionized with the discovery that two related G-protein-coupled receptors GPCRs needed to dime-rize to form the functional GABAB...

Gfap

Codistribution of GABAB-R1 and CREB2 in neurons. a Codistribution of GABAB-R1 and CREB2 in rat primary cortical cultures. Fixed rat-cortical neurons E17 were stained with primary antibodies for GABAB-R1 and CREB2. Images were viewed for GABAB-R1 green and CREB2 red , and the images were merged bar 10 mm . Arrowheads indicate areas of distinct codistribution for the two proteins in the distal dendrites. b Codistribution of GABAB-R1 and CREB2 in rat-cerebellar cortex. Fluorescence was...