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Receptors-GABA_A and Glycine

GABA and glycine ionotropic receptors are selectively permeable to Cl- (reversal potential near -70 mV). When they open, they cause the neuron to hyperpolarize and therefore drive the membrane potential away from the threshold for firing an action potential. GABA, like glutamate, also binds to and activates a GPCR. In contrast, glycine only binds to ionotropic receptors.

GABA Receptors

The ionotropic and G-protein coupled GABA receptors are referred to as GABA_A and GABA_B, respectively. Some of the main features of GABA_A and GABA_B receptors are as follows:

Characteristics of GABA_A Receptor

The GABA_A receptor is composed of five subunits that each contain four membrane spanning domains. GABA_A subunits are highly related to those of the nicotinic ACh receptor. Important differences exist to produce a channel that permits the permeation of the negatively charged Cl^- ion. Specifically, there are positively charged amino acids placed at strategic positions within the channel portion of the receptors that permit Cl^- passage. The different subunits of the GABA_A receptor are responsible for the binding of different drugs.

1. GABA binds predominantly to the alpha subunit (Figure 13.11).
   
2. Benzodiazepines (like Valium and Librium) bind to the gamma subunit.
   
3. Barbiturates (Phenobarbital and secobarbital) bind to both the alpha and beta subunits.
   
4. Picrotoxin blocks ion flow through the receptor (Figure 13.11).
   

The pharmacology of GABA_A receptors is complex and clinically important. When GABA is released into the synapse, it binds to a population of the available receptors, but typically not all of them (Figure 13.12). If benzodiazepines are present, the effectiveness of GABA binding to its receptor is increased significantly (Figure 13.13). Therefore, effective doses of benzodiazepines enhance the ability of GABA to hyperpolarize the neuron by increasing the number of GABA receptors that open at a fixed concentration of GABA. Inhibition is produced by increasing the amount of Cl^- that flows into the neuron (Figure 13.12 and 13.13). Recognize that benzodiazepines themselves do not open the receptor but simply enhance GABA binding. Barbiturates also produce their sedative effects by increasing the effectiveness of GABA binding to its receptor. The naturally occurring toxin called picrotoxin is a potent inhibitor of the GABA_A receptor and works by preventing Cl^- flow through the receptor (Figure 13.11).

Glycine Receptor

The glycine receptor, like the GABA_A receptor also permits the influx of Cl^- into neurons and displays a reversal potential near -70 mV. This Cl^--permeable glycine receptor can be blocked by the rat poison strychnine. The mature glycine receptor is constructed from mixtures of at least two subunits each of which has four membrane spanning domains.

G-protein Coupled Glutamate and GABA_B Receptors

Glutamate GPCRs are members of a large family of receptors that couple with G proteins to produce their effects. These receptors like those for serotonin, norepinephrine, epinephrine, muscarinic ACh, and dopamine, produce the large majority of their effects through alterations in the activity of metabolic enzymes and not by directly opening ion channels in the membranes. All of these receptors are single polypeptides that span the membrane seven times (See Fig. 11.10. and Fig. 13.8).

The glutamate GPCR's best known effects are the activation of phospholipase C which generates inositol-trisphosphate (IP₃) and diacylglycerol (DAG) from the precursor lipid phosphatidylinositol bisphosphate (See Figure 13.8). Inositol-trisphosphate binds to receptors on intracellular organelles causing the release of Ca²⁺. Among several other things, increased Ca²⁺ along with diacylglycerol lead to the activation of protein kinase C which produces a variety of alterations in the enzymatic machinery of the cell including the regulation of ion channels that affect the electrical properties of the neuron.

The GABA_B receptor, like the glutamate GPCR, produces its effects not by directly opening ion channels, but by coupling to G-proteins and enzymes that influence metabolites within the neuron. Reported effects include alterations (either increases or decreases) in cAMP levels, increases in K⁺-conductance, and decreases in Ca²⁺-conductance. Some of the ion channel effects detected are due to the components of the activated G-protein binding directly to ion channels, influencing their properties (See Figure 6.5).

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