The NMDA receptor is one of two main kinds of receptors activated by glutamate.
The other main kind of glutamate receptor is called the AMPA receptor.
These two receptors—each with distinct physiological properties—
often coexist at the same synapse.
Shown here is a model synapse in the CA1 region of the hippocampus
containing both types of receptors.
Weak electrical stimulation of the presynaptic neuron causes the release
of glutamate from the axon terminal.
This glutamate binds to both AMPA and NMDA receptors.
Although both NMDA and AMPA receptors are permeable to sodium and
potassium ions, weak stimulation normally activates only the AMPA receptors,
resulting in a slight depolarization of the postsynaptic neuron.
When glutamate binds to the NMDA receptor at slightly depolarized
or resting membrane voltages, very few ions flow through the channel.
This low conductance occurs because the pore of the channel is blocked
by magnesium ions, which prevents other ions from passing freely through the channel.
Under such conditions, the EPSP will be mediated entirely by the AMPA receptors.
Given a stimulus of sufficient strength or frequency, AMPA receptors can depolarize
the membrane sufficiently to expel the magnesium from the NMDA channel.
The NMDA channel now actively responds to glutamate, admitting not only sodium ions,
but large amounts of calcium as well.
The calcium acts as an important
second messenger, activating several intracellular signaling cascades.
For example, some calcium binds to calmodulin, and this complex in turn activates
several protein kinases, including calcium/calmodulin-dependent protein kinase,
or CAM kinase.
CAM kinase affects AMPA receptors in two ways.
First, it phosphorylates AMPA receptors already present in the
dendritic spine membrane, thereby increasing their conductance to sodium ions.
CAM kinase also promotes movement of AMPA receptors from intracellular stores into
the membrane, making more receptors available to stimulate the spine.
As a result of the increase in the number of AMPA receptors,
the response to a stimulus of a given strength will be stronger than it was
before the NMDA receptors were activated.
In this regard, the synapse is said to be “enhanced,”
and this physiological change is thought to be one of the mechanisms
underlying the expression of long-term potentiation, or LTP.