GABA and glycine as neurotransmitters: a brief history - PubMed (original) (raw)

GABA and glycine as neurotransmitters: a brief history

N G Bowery et al. Br J Pharmacol. 2006 Jan.

Abstract

gamma-Aminobutyric acid (GABA) emerged as a potentially important brain chemical just over 50 years ago, but its significance as a neurotransmitter was not fully realized until over 16 years later. We now know that at least 40% of inhibitory synaptic processing in the mammalian brain uses GABA. Establishing its role as a transmitter was a lengthy process and it seems hard to believe with our current knowledge that there was ever any dispute about its role in the mammalian brain. The detailed information that we now have about the receptors for GABA together with the wealth of agents which facilitate or reduce GABA receptor mechanisms make the prospects for further research very exciting. The emergence of glycine as a transmitter seems relatively painless by comparison to GABA. Perhaps this is appropriate for the simplest of transmitter structures! Its discovery within the spinal cord and brainstem approximately 40 years ago was followed only 2 years later by the proposal that it be conferred with 'neurotransmitter' status. It was another 16 years before the receptor was biochemically isolated. Now it is readily accepted as a vital spinal and supraspinal inhibitory transmitter and we know many details regarding its molecular structure and trafficking around neurones. The pharmacology of these receptors has lagged behind that of GABA. There is not the rich variety of allosteric modulators that we have come to readily associate with GABA receptors and which has provided us with a virtual treasure trove of important drugs used in anxiety, insomnia, epilepsy, anaesthesia, and spasticity, all stemming from the actions of the simple neutral amino acid GABA. Nevertheless, the realization that glycine receptors are involved in motor reflexes and nociceptive pathways together with the more recent advent of drugs that exhibit some subtype selectivity make the goal of designing selective therapeutic ligands for the glycine receptor that much closer.

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Figures

Figure 1

Figure 1

Action of GABA on membrane potential and resistance of neocortical neurones. In each trace, two downward pulses were evoked by equal 20 ms pulses of current (hyperpolarizing in a, c and e and depolarizing in b, d and f) applied before and near the peak IPSP elicited by stimulating the cortical surface. Note the sharp drop in resistance during the IPSP (smaller responses in a and b); GABA produced a similar drop in resistance (smaller initial responses in c and d) as well as a hyperpolarization, indicated by the downward shift in the resting potential (arrows). Traces (e) and (f) show the recovery from the effects of GABA (taken from Dreifuss et al. (1969). Exp Brain Res 9: 137–154, with permission).

Figure 2

Figure 2

Diagrammatic representation of the rationale for determining whether the depolarizing action of GABA on sympathetic ganglion neurones would extend to the sympathetic terminals to provide a model for central presynaptic inhibition. While a Cl−-dependent action might exist on the terminals, what was detected by examining the influence of GABA on transmitter outflow was an action that was independent of Cl− and insensitive to recognized GABA antagonists.

Figure 3

Figure 3

Heterodimeric structure of the GABAB receptor. The two 7TM receptor subunits (GABAB1 and GABAB2) are coupled via their intracellular C-termini. The binding domain for GABA is located in the extracellular domain of GABAB1. The heptahelical domain of GABAB2 contains an allosteric modulator site as well as the G-protein-coupling site. Neither of these appear to be present in the GABAB1 subunit. The receptor is coupled indirectly to K+ and Ca2+ channels, the former of which predominates postsynaptically while the latter is mainly presynaptic in origin. Note that the ligand binding domain is believed to be similar to the leucine/isoleucine/valine-binding protein (LIV-BP), one of the bacterial periplasmic binding proteins (modified from The GABA receptors, in Encyclopedia of Neuroscience, 3rd edn. Amsterdam: Elsevier, with permission).

Figure 4

Figure 4

The glycine receptor. This diagram shows two juxtaposed _α_1 subunits of the glycine receptor based on a homology model with the acetylcholine-binding protein and the TM domains taken from the nicotinic acetylcholine receptor. The N-terminal domains are shown in blue with the Cys loops depicted in yellow. The TM domains TM1, 3 and 4 are shown in green and the ion channel lining TM2 is shown in orange. The model illustrates the position of histidines 107 and 109 (orange) and their ability to coordinate a Zn2+ ion (red) at the interface between two adjacent _α_1 subunits. The alignments were generated using Deep View version 3.7.

Figure 5

Figure 5

The glycinergic synapse. Schematic representation of a typical glycinergic synapse. The glycine receptors are shown as pentamers of stoichiometry 3_α_ : 2_β_ and also the more recent preferred stoichiometry of 2_α_ : 3_β_. The receptors are anchored via the β subunits to gephyrin and thus to the microfilaments and microtubules. Presynaptic glycine is packaged into vesicles via the vesicular inhibitory amino-acid transporter (VIAAT) before release. After dissociation from the receptor, either of two discretely localized glycine transporters (GlyT1 or 2) sequester the glycine, which can then be re-packaged into synaptic vesicles or hydrolysed via the glycine cleavage system (GCS).

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