Neuroscience Online

Section I: Cellular and Molecular Neurobiology 13. Amino Acid Neurotransmitters Part 3 of 5 Neal Waxham, Ph.D.

Receptors for Amino Acid Neurotransmitters

Glutamate Receptors

Ionotropic glutamate receptors open channels that cause the cell to depolarize and are therefore excitatory (driving the membrane potential towards firing an action potential). The reversal potential (near 0 mV) of the EPSP indicates that glutamate opens receptors selectively permeable to cations (Na⁺, K⁺, and Ca²⁺).

Opening of non-NMDA receptors causes the majority of the excitatory postsynaptic potentials (EPSPs) in the nervous system. This receptor is mainly permeable to Na⁺ and K⁺ (Figure 13. 9). The structure of non-NMDA receptors loosely resembles the nicotinic ACh receptor, although glutamate receptors have some unique features. Four subunits, each having only three membrane spanning segments (as opposed to four for the nicotinic ACh receptor), combine to produce the functional receptor. Many different subunit isoforms have been cloned and characterized and mixing different subunits can significantly alter the properties of the mature non-NMDA receptor. As one example, some subunit mixtures are permeable to Ca²⁺ as well as Na⁺ and K⁺. Although it is premature to dwell on these details, future development of drugs that bind to specific glutamate receptor subtypes will find important clinical applications.

Figure 13.9

Figure 13.10

NMDA receptors are unique in the nervous system and exhibit two important characteristics. First, they have a high permeability to Ca²⁺ (although they are also permeable to Na⁺ and K⁺), and when they open significant increases in the level of Ca²⁺ can be detected in the neuron (Figure 13.10). Increased levels of Ca²⁺ activate a wide variety of enzyme systems that alter both the short- and long-term response of the neurons (recall that activation of this receptor is required for the induction of long-term potentiation). Glycine, which is normally always present in the extracellular space, is also required for the NMDA receptor to open. Second, NMDA receptors require both ligand binding and membrane depolarization to open. The channel associated with the NMDA receptor binds Mg²⁺, stopping ions from flowing through the channel (Figure 13.10). Mg²⁺ can be displaced from the channel by depolarizing the membrane. This unique property imparts to the receptor the capacity to sense the membrane potential and open only when the neuron is depolarized. The ability to sense presynaptic activity (through the binding of released glutamate) and postsynaptic activity (through sensing membrane potential) means the NMDA receptor associates the two activities. This property (associativity) fulfills one of the central criteria for a molecule involved in learning. Apparently, Ca²⁺-influx through the NMDA receptor initiates a set of biochemical changes so that the neuron remembers the conjoint activity and responds differently when activated in the future. Like the non-NMDA receptor, the mature NMDA receptor is constructed from a mixture of different subunits, again each having three transmembrane segments.

Test Your Knowledge

15. NMDA receptors:

A. Require membrane depolarization to permit ion flow B. Require membrane depolarization to permit ion flow and are NOT permeable to Ca2+ C. Are NOT permeable to Na+ D. Bind to G-proteins E. Have a seven-membrane spanning structure consisting of a single subunit