Glycine · Grey Matter

Glycine is the main fast inhibitory neurotransmitter of the spinal cord and brainstem, where it keeps motor circuits from overreacting, and in the forebrain it has a second job as the co-agonist that the NMDA receptor needs before glutamate can open it.

Glycine. Glycine is the main fast inhibitory neurotransmitter of the spinal cord and brainstem, where it keeps motor circuits from overreacting, and in the forebrain it has a second job as the co-agonist that the NMDA receptor needs before glutamate can open it.

As a transmitter it is released by inhibitory interneurons and acts on glycine receptors, chloride channels of the ionotropic family closely related to the GABA-A receptor. Opening them hyperpolarises or shunts the receiving cell within milliseconds. In the spinal cord this inhibition shapes reflexes and the alternation of flexor and extensor muscles, and it lets one muscle relax while its opponent contracts. It is cleared by its own transporters, GlyT2 at inhibitory synapses and GlyT1 elsewhere.

Blocking it releases the reflexes. Strychnine binds the glycine receptor and blocks it, so every sensory input triggers uncontrolled muscle contraction; the convulsions of strychnine poisoning are inhibition lost at the spinal level.

It is a gate for the NMDA receptor. Glycine (or D-serine) must occupy a separate site on the NMDA receptor for glutamate to open it; GlyT1 near those synapses keeps that site from being saturated, which is why GlyT1 inhibitors have been studied as a way to boost NMDA function.

The two roles use different receptors, so a drug acting on one leaves the other largely untouched.

Glycine is the brake of the spinal cord and a key in the brain's learning lock.

The same small amino acid inhibits movement circuits through its own receptor and permits plasticity through the NMDA receptor.

Questions: Why does the NMDA receptor need glycine as well as glutamate? The NMDA receptor is built from GluN1 subunits, which bind glycine (or D-serine), and GluN2 subunits, which bind glutamate, and the channel opens only when both sites are occupied. Johnson and Ascher showed in 1987 that glycine at low concentrations strongly increases NMDA responses, and later work found it to be required. The co-agonist site is a second key: glutamate signals the synapse's activity, and the level of glycine or D-serine, partly set by glial transporters and release, adjusts how readily NMDA receptors in a region can open. This glycine site is separate from the glycine receptor that inhibits spinal neurons, and it is insensitive to strychnine. Why does strychnine cause violent muscle spasms? In the spinal cord and brainstem, inhibitory interneurons release glycine onto motor neurons, opening glycine receptors (chloride channels) that keep the motor neurons from responding to every input and let opposing muscles relax in turn. Strychnine binds the glycine receptor at the glycine site and blocks it. With that inhibition gone, any sensory input (a touch, a sound) drives motor neurons unchecked, and whole groups of muscles contract together in painful spasms. The brain stays largely unaffected at first, since forebrain inhibition relies mostly on GABA, which is why consciousness is usually preserved.