Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

Abstract

The GABA A receptors (GABARs) are chloride-permeable ligand-gated ion channels responsible for fast inhibitory neurotransmission. These receptors are structurally heterogeneous, and in mammals can be formed from a combination of sixteen different subunit subtypes. Much of this variety comes from the six different α subunit subtypes. All neuronal GABARs contain an α subunit, and the identity of the α subtype affects the pharmacological properties of the receptors. The expression of each of the different α subtypes is regulated developmentally and regionally and changes with both normal physiological processes such development and synaptic plasticity, and pathological conditions such as epilepsy. In order to understand the functional significance of this structural heterogeneity, we examined the effect of the α subtype on the receptor's response to GABA. Each of the six α subtypes was transiently co-expressed with the β3 and γ2L subunits in mammalian cells. The sensitivity to GABA was measured with whole-cell recordings. We also determined the activation, deactivation, desensitization, and recovery kinetics for the six isoforms using rapid-application recordings from excised macropatches. We found unique characteristics associated with each α subunit subtype. These properties would be expected to influence the post-synaptic response to GABA, creating functional diversity among neurons expressing different α subunits.

Developmental Modulation of GABAA Receptor Function by RNA Editing

“…Although all ␣3␤3␥2L currents activated and desensitized very slowly compared with the more widely studied ␣1 subunitcontaining receptors (Barberis et al, 2007;Picton and Fisher, 2007), nonedited ␣3(I)␤3␥2L currents activated more rapidly than edited ␣3(M)␤3␥2L currents (Fig. 2 B, C).…”

“…2; supplemental Table 1, available at www.jneurosci.org as supplemental material). As previously described (Barberis et al, 2007;Picton and Fisher, 2007), high GABA concentrations were required to activate ␣3␤3␥2L receptors, with peak current EC 50 s of 65 and 153 M, for nonedited ␣3(I)␤3␥2L and edited ␣3(M)␤3␥2L receptors, respectively. However, because the GABA-mediated depolarizations seen during development may last for several seconds (Ben-Ari et al, 2007), we also measured the residual current at the end of a 4 s application of varying concentrations of GABA to better assess the responses to slow GABA fluctuations.…”

Strength and duration of perisomatic GABAergic inhibition depend on distance between synaptically connected cells

“…Furthermore, electrotonic filtering of inhibitory signals did not contribute to distancedependent uIPSC slowdown (30). PIIs formed putative synapses at equal electrotonic distances between synapse location and GC soma ( sites, GCs predominantly express α1, α2, and α3, which confer fast, intermediate, and slow deactivation, respectively (31)(32)(33). We therefore probed α-immunoreactivity in γ2-subunit-immunopositive puncta, a marker for GABAergic synapses, in close vicinity of intracellularly labeled PII axons (Fig.…”

Synaptic-Type α1β2γ2L GABAA Receptors Produce Large Persistent Currents in the Presence of Ambient GABA and Anesthetic Drugs

“…The conventional view is that synaptic-type receptors are minimally affected by the presence of low ambient GABA. Indeed, the concentration of extracellular GABA (Houston et al, 2012) is several tens of folds lower than the apparent affinity to GABA of synaptic subtypes of GABA A receptors (Li et al, 2006;Picton and Fisher, 2007).…”