Influence of GABA_AR Monoliganded States on GABAergic Responses

Abstract

To reach the open state, the GABA(A) receptor (GABA(A)R) is assumed to bind two agonist molecules. Although it is currently believed that GABA(A)R could also operate in the monoliganded state, the gating properties of singly bound GABA(A)R are poorly understood and their physiological role is still obscure. In the present study, we characterize for the first time the gating properties of singly bound GABA(A)Rs by using a mutagenesis approach and we propose that monoliganded GABA(A)R contribute in shaping synaptic responses. At saturating GABA concentrations, currents mediated by recombinant GABA(A)Rs with a single functional binding site display slow onset, fast deactivation kinetics, and slow rate of desensitization-resensitization. GABA(A)Rs with two binding sites activated by brief pulses of subsaturating GABA concentrations (in the range of the GABA concentration profile in the synaptic cleft) could also mediate fast deactivating currents, displaying deactivation kinetics similar to those mediated by GABA(A)Rs with a single functional binding site. Model simulations of receptors activated by realistic synaptic GABA waves revealed that a considerable proportion of GABA(A) receptors open in the monoliganded state during synaptic transmission, therefore contributing in shaping IPSCs.

GABAA Receptors Predict Aversion-Related Brain Responses: An fMRI-PET Investigation in Healthy Humans

“…The primary fast-acting target of GABA is the ionotropic GABA A R, and it is well-known to be involved in the inhibition of cellular activity, particularly through its increasing of inhibitory postsynaptic potentials (Petrini et al, 2011). This is in line with the notion that GABA A Rs within aversion interaction sensorimotor subregions may predict enhanced inhibition, as reflected by lower signal change differences from the interaction contrasts in individuals with higher GABA A R BPs.…”

γ-Aminobutyric Acid Type A α4, β2, and δ Subunits Assemble to Produce More Than One Functionally Distinct Receptor Type

“…both GABA binding sites renders the receptor inactive in the presence of GABA (Petrini et al, 2011). The db3a4b3a4 order of a4b3d receptors was proposed previously in a study employing atomic force microscopy imaging complexes between epitope-tagged receptors and antibodies in HEK cells (Barrera et al, 2008).…”

“…These were a4(F63C), d(F74C) (both in loop D at the "-" interface of the extracellular domain), and d(T269Y) (T69Y in the second membrane-spanning domain). The mutations to loop D residues were made to test the contributions of a4 and d subunits to receptor activation by GABA (Petrini et al, 2011). The d(T269Y) mutation was used to confer resistance to picrotoxin (Gurley et al, 1995).…”

“…To explore the configuration of the a4b2d receptor, we mutated a conserved phenylalanine residue in loop D to cysteine. This mutation in the a1 subunit (a1F64C) has been shown to effectively abolish activation by GABA without affecting gating by PEB in a1b1g2 receptors (Petrini et al, 2011).…”

2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors

“…Within this context, several of the present observations raise the intriguing possibility that, in the presence of 2-AEMP, GABA-elicited receptor activation occurs only from a mono-liganded state (i.e., only one site occupied by GABA). Previous studies have shown that GABA A receptors can open from monoliganded as well as multiliganded states (Twyman et al, 1990;Jones and Westbrook, 1995;Petrini et al, 2011). In particular, Petrini et al (2011) have shown that monoliganded channels activate slowly and desensitize minimally by comparison with multiliganded channels.…”