The membrane of the postsynaptic neuron contains large numbers of receptor proteins, also shown in Figure 1A. The molecules of these receptors have two important components: (1) a binding component that protrudes outward from the membrane into the synaptic cleft— here it binds the neurotransmitter coming from the pre synaptic terminal—and (2) an intracellular component that passes all the way through the postsynaptic mem brane to the interior of the postsynaptic neuron. Receptor activation controls the opening of ion channels in the postsynaptic cell in one of two ways: (1) by gating ion channels directly and allowing passage of specified types of ions through the membrane, or (2) by activating a “second messenger” that is not an ion channel but instead is a molecule that protrudes into the cell cytoplasm and activates one or more substances inside the postsynaptic neuron. These second messengers increase or decrease specific cellular functions.
Fig1. Physiological anatomy of a chemical synapse (A) and an electrical synapse (B).
Most of the synapses used for signal transmission in the central nervous system of the human being are chemical synapses. In these synapses, the first neuron secretes at its nerve ending synapse a chemical substance called a neurotransmitter (often called a transmitter substance), and this transmitter in turn acts on receptor proteins in the membrane of the next neuron to excite the neuron, inhibit it, or modify its sensitivity in some other way. More than 40 important neurotransmitters have been discovered thus far. Some of the best known are acetylcholine, norepinephrine, epinephrine, histamine, gamma-aminobutyric acid (GABA), glycine, serotonin, and glutamate.
Neurotransmitter receptors that directly gate ion channels are often called ionotropic receptors, whereas those that act through second messenger systems are called metabotropic receptors.
Ion Channels. The ion channels in the postsynaptic neuronal membrane are usually of two types: (1) cation channels that most often allow sodium ions to pass when opened but sometimes also allow potassium and/or calcium ions to pass, and (2) anion channels that mainly allow chloride ions to pass but allow minute quantities of other anions to pass as well.
The cation channels that conduct sodium ions are lined with negative charges. These charges attract the positively charged sodium ions into the channel when the channel diameter increases to a size larger than that of the hydrated sodium ion. However, those same negative charges repel chloride ions and other anions and prevent their passage.
For the anion channels, when the channel diameters become large enough, chloride ions pass into the channels and on through to the opposite side, whereas sodium, potassium, and calcium cations are blocked, mainly because their hydrated ions are too large to pass.
We will learn later that when cation channels open and allow positively charged sodium ions to enter, the positive electrical charges of the sodium ions will in turn excite this neuron. Therefore, a neurotransmitter that opens cation channels is called an excitatory transmitter. Conversely, opening anion channels allows negative electrical charges to enter, which inhibits the neuron. Therefore, neurotransmitters that open these channels are called inhibitory transmitters.
When a neurotransmitter activates an ion channel, the channel usually opens within a fraction of a millisecond; when the transmitter substance is no longer present, the channel closes equally rapidly. The opening and closing of ion channels provide a means for very rapid control of postsynaptic neurons.
“Second Messenger” System in the Postsynaptic Neuron. Many functions of the nervous system—for instance, the process of memory—require prolonged changes in neurons for seconds to months after the initial transmitter substance is gone. The ion channels are not suitable for causing prolonged postsynaptic neuronal changes because these channels close within milliseconds after the transmitter substance is no longer present. However, in many instances, prolonged postsynaptic neuronal excitation or inhibition is achieved by activating a “second messenger” chemical system inside the postsynaptic neuronal cell itself, and then it is the second messenger that causes the prolonged effect.
There are several types of second messenger systems. One of the most common types uses a group of proteins called G proteins. Figure 2 shows a membrane receptor G protein. The inactive G protein complex is free in the cytosol and consists of guanosine diphosphate (GDP) plus three components: an alpha (α) component that is the activator portion of the G protein, and beta (β) and gamma (γ) components that are attached to the alpha component. As long as the G protein complex is bound to GDP, it remains inactive.
Fig2. The “second messenger” system by which a transmitter substance from an initial neuron can activate a second neuron by first causing a transformational change in the receptor that releases the activated alpha (α) subunit of the G protein into the second neuron’s cytoplasm. Four subsequent possible effects of the G protein are shown, including 1, opening an ion channel in the membrane of the second neuron; 2, activating an enzyme system in the neuron’s membrane; 3, activating an intracellular enzyme system; and/or 4, causing gene transcription in the second neuron. Return of the G protein to the inactive state occurs when guanosine triphosphate (GTP) bound to the α subunit is hydrolyzed to guanosine diphosphate (GDP) and the β and γ subunits are reattached to the α subunit.
When the receptor is activated by a neurotransmitter, following a nerve impulse, the receptor undergoes a conformational change, exposing a binding site for the G protein complex, which then binds to the portion of the receptor that protrudes into the interior of the cell. This process permits the α subunit to release GDP and simultaneously bind guanosine triphosphate (GTP) while separating from the β and γ portions of the complex. The separated αGTP complex is then free to move within the cytoplasm of the cell and perform one or more of multiple functions, depending on the specific characteristic of each type of neuron. The following four changes that can occur are shown in Figure 2:
1. Opening specific ion channels through the post synaptic cell membrane. Shown in the upper right of the figure is a potassium channel that is opened in response to the G protein; this channel often stays open for a prolonged time, in contrast to rapid closure of directly activated ion channels that do not use the second messenger system.
2. Activation of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP) in the neuronal cell. Recall that either cAMP or cGMP can activate highly specific metabolic machinery in the neuron and, therefore, can initiate any one of many chemical results, including long term changes in cell structure itself, which in turn alters long-term excitability of the neuron.
3. Activation of one or more intracellular enzymes. The G protein can directly activate one or more intracellular enzymes. In turn, the enzymes can cause any one of many specific chemical functions in the cell.
4. Activation of gene transcription. Activation of gene transcription is one of the most important effects of activation of the second messenger systems because gene transcription can cause formation of new proteins within the neuron, thereby changing its metabolic machinery or its structure. Indeed, it is well known that structural changes of appropriately activated neurons do occur, especially in long term memory processes.
Inactivation of the G protein occurs when the GTP bound to the α subunit is hydrolyzed to GDP. This action causes the α subunit to release from its target protein, thereby inactivating the second messenger systems, and then to combine again with the β and γ subunits, returning the G protein complex to its inactive state.
It is clear that activation of second messenger systems within the neuron, whether they be of the G protein type or of other types, is extremely important for changing the long-term response characteristics of different neuronal pathways. We will return to this subject in more detail in Chapter 58 when we discuss memory functions of the nervous system.
