(Section 1, Chapter 13, Part 3) Neuroscience Online: An Electronic Textbook for the Neurosciences | Department of Neurobiology and Anatomy - The University of Texas Medical School at Houston

Receptors for Amino Acid Neurotransmitters

Receptors for each of the amino acid neurotransmitters can either directly open an ion channel (ionotropic) or couple to a G-protein (G-protein coupled receptor; GPCR) except for glycine. There is no known GPCR for glycine and all of glycine's effects are mediated through an ion channel permeable to Cl^-. In contrast, glutamate and GABA can produce fast responses by directly opening ion channels and can produce slow responses by activating receptors coupled to G-proteins. Examples of ionotropic receptors and GPCRs are compared in Figures 13.7 and 13.8, respectively.

Glutamate Receptors

There are at least three distinct types of glutamate receptors. Two are ionotropic since glutamate binding directly opens an ion channel and the other is a GPCR, producing alterations in intracellular messengers (Figures 13.7 and 13.8). These three distinct types of glutamate receptors have been characterized by using agonists that specifically activate each type. The agonists and the subset of glutamate receptors they activate are termed:

NMDA (N-methyl-D-aspartate, a synthetic compound that acts as an agonist for this particular glutamate receptor subtype),
non-NMDA (also known as kainate/AMPA receptors since these agonists activate this receptor subtype), and
G-protein coupled glutamate receptor.


Figure 13.7		Figure 13.8

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

Question 1
A
B
C
D
E

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 seven-membrane spanning structure consisting of a single subunit

NMDA receptors:

A. Require membrane depolarization to permit ion flow This answer is CORRECT!

A critical feature of the NMDA receptor is that at the resting potential of the neuronal membrane it is inactive even if glutamate is bound. When glutamate is bound and the membrane potential moves towards positive the receptor becomes unblocked, permitting ion flow. This sensitivity to membrane potential is caused by the NMDA receptor's Mg²⁺-binding site. At resting membrane potentials, extracellular Mg²⁺ sits in the channel plugging it and inhibiting ion flow. At more positive membrane potentials the Mg²⁺ ion is force out of the channel, permitting ions to flow. Again, both glutamate bound to the receptor and membrane depolarization is required for NMDA receptors 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 seven-membrane spanning structure consisting of a single subunit

NMDA receptors:

A. Require membrane depolarization to permit ion flow

B. Require membrane depolarization to permit ion flow and are NOT permeable to Ca²⁺ This answer is INCORRECT.

NMDA receptors are permeable to the divalent cation Ca²⁺. Many of the important effects that activation of NMDA receptors has in the nervous system are related to the fact that it permits Ca²⁺-influx. These can be positive outcomes, like during proper activation of Ca²⁺-dependent enzymes leading to changes important for regulating neuronal function. Or negative outcomes like during a stroke where lack of blood flow produces hyper activation of NMDA receptors, excess Ca²⁺-influx and excess Ca²⁺-dependent enzyme stimulation.

C. Are NOT permeable to Na⁺

D. Bind to G-proteins

E. Have seven-membrane spanning structure consisting of a single subunit

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⁺ This answer is INCORRECT.

NMDA receptors are permeable to Na⁺ in addition to Ca²⁺. When activated Na⁺ and Ca²⁺ flow into the cell and K⁺ flows out of the cell through NMDA receptors (and additional types of channels as well).

D. Bind to G-proteins

E. Have seven-membrane spanning structure consisting of a single subunit

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 This answer is INCORRECT.

NMDA receptors are themselves ion channels. Glutamate binding to these receptors cause direct opening of the channel, thus producing rapid discrete responses. There is no direct coupling of NMDA receptors to G-proteins.

E. Have seven-membrane spanning structure consisting of a single subunit

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 seven-membrane spanning structure consisting of a single subunit This answer is INCORRECT.

NMDA receptors are multi-subunit protein complexes that form an ion channel in the membrane. Five protein subunits each of which crosses the membrane 3 times congregate into the mature NMDA receptor complex. G-protein coupled receptors are composed of a single subunit that has seven membrane-spanning segments.

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