GABA-A receptor · Grey Matter

The GABA-A receptor is the chloride channel opened by GABA, and it delivers the fast inhibition of the brain: within a millisecond of binding it clamps the receiving neuron near or below rest for a few to a few tens of milliseconds.

GABA-A receptor. The GABA-A receptor is the chloride channel opened by GABA, and it delivers the fast inhibition of the brain: within a millisecond of binding it clamps the receiving neuron near or below rest for a few to a few tens of milliseconds.

It is built from five subunits around a pore permeable to chloride (and some bicarbonate). Whether opening it hyperpolarises or merely holds the voltage depends on the chloride gradient: in mature neurons, where the transporter KCC2 keeps chloride low inside, chloride flows in and the cell is pulled toward about −70 mV or below. Even where the voltage barely moves, the open channels add a conductance that drains away excitatory current (shunting inhibition). Synaptic GABA-A currents typically decay in about 5 to 10 ms at fast synapses and longer elsewhere; receptors outside synapses, sensitive to low ambient GABA, add a steady background (tonic) inhibition.

Its subunit mix decides its drugs. Benzodiazepines bind between an alpha and a gamma subunit and make GABA more effective; barbiturates, many anaesthetics, neurosteroids and alcohol act at other sites on the same receptor.

Placement decides function. Receptors on the cell body and axon initial segment, driven by basket and chandelier interneurons, veto output and set spike timing; receptors on dendrites control what inputs reach the soma.

The sign can flip. Where chloride is high inside (in immature neurons, see the GABA switch, or after intense activity) opening it depolarises.

The GABA-A receptor is a brake pedal whose force depends on the chloride gradient.

Drugs press it harder; a changed gradient can make the same pedal push the other way.

Questions: How do benzodiazepines stop a seizure? Benzodiazepines bind GABA-A receptors at a site between an alpha and a gamma subunit, apart from where GABA binds, and make GABA open the channel more often. They amplify the inhibition the interneurons are already delivering and need GABA present to act, which is why they are relatively safe on their own and why they act fast in an emergency. Stronger inhibition restores the brake on the synchronised firing of a seizure. Their limits follow from the same mechanism: receptors are internalised during prolonged seizures, so the drugs work best given early, and where chloride has built up inside neurons GABA itself inhibits less. How can GABA inhibit a neuron even when it barely changes the voltage? When the chloride equilibrium potential sits close to the resting voltage, opening GABA-A channels moves the voltage little, but the open channels still make the membrane leakier. Excitatory current arriving at the same moment then escapes through that leak instead of charging the membrane, so an input that would have reached threshold falls short. This is shunting inhibition: it divides the effect of excitation more than it subtracts from the voltage. It is strongest when the GABA synapses sit between the excitatory inputs and the spike initiation zone, on the soma or the axon initial segment. How do benzodiazepines, barbiturates and vigabatrin strengthen inhibition in different ways? Benzodiazepines bind the GABA-A receptor between its alpha and gamma subunits and make its chloride channel open more often when GABA is present, so they amplify inhibition only where GABA is released. Barbiturates bind other sites on the same receptor and make each opening last longer, and at high doses they open it without GABA, which makes them more powerful and more dangerous. Vigabatrin acts upstream of the receptor: it permanently blocks GABA transaminase, the enzyme that breaks GABA down, so more GABA is available to be released. Why can GABA excite the neurons of a newborn's brain? GABA opens a chloride channel, and whether that inhibits depends on how much chloride is inside the cell. Immature neurons express the transporter NKCC1, which loads chloride in, so when GABA-A channels open chloride flows out and the membrane depolarises, sometimes enough to help fire the cell. As neurons mature they express KCC2, which pumps chloride out; internal chloride falls and GABA becomes hyperpolarising or shunting. In rodents the switch happens over the first one to two postnatal weeks, and in humans KCC2 rises steeply around full-term birth, so the newborn brain sits close to the transition. Why does GABA produce both a fast and a slow inhibition? GABA acts on two different receptors. The GABA-A receptor is a chloride channel that opens within a millisecond, and its current decays over roughly 5 to 10 ms at fast synapses (longer at others). The GABA-B receptor is metabotropic: it acts through a G protein that opens GIRK potassium channels, so the inhibition peaks after about 50 to 250 ms and decays over 100 to 500 ms. GABA-B receptors sit mostly outside the synapse and need GABA to spill over, so they come into play when inhibitory cells fire strongly or together, adding a long tail of quiet after intense inhibition.