Psychiatric Annals

PSYCHOPHARM PSNAPSHOTS 

Two Receptor Superfamilies Mediate Fast and Slow Neurotransmission

Stephen M Stahl, MD, PhD

Abstract

Neuronal receptors are the sites where neurotransmitters act and are also the targets for most psychotropic drugs. Knowledge about neurotransmitter receptors had skyrocketed in recent years with multiple receptors now being demonstrated for every known neurotransmitter. When a neurotransmitter has multiple receptors, they are called receptor subtypes. Although an ever-increasing array of dozens of various neurotransmitter receptor subtypes is being discovered (eg, multiple serotoniii receptor subtypes), all of them can be reduced to two simple classes called "superfamities."

The first superfamily mediates "slow neurolransmission" (Figure !land is named the ''seven transmembrane-G protein linked-seo ond messenger system" superfamily (Figure 2). Most neurotransmitter receptors for most psychotropic drugs belong to this class. Notable examples are subtypes of serotonin, norepinephrine, and dopamine receptors.

The other superfamily mediates "fast neurotransmission" (Figure 1) and is named the "ligand-gated ion channel" superfamily (Figures 3 and 4). An important example of this receptor is the GABA (Gamma-ainino-butyric acid) receptor linked both to benzodiazepine receptors and an inhibitory chloride ion channel (Figures 5 and 6).…

Neuronal receptors are the sites where neurotransmitters act and are also the targets for most psychotropic drugs. Knowledge about neurotransmitter receptors had skyrocketed in recent years with multiple receptors now being demonstrated for every known neurotransmitter. When a neurotransmitter has multiple receptors, they are called receptor subtypes. Although an ever-increasing array of dozens of various neurotransmitter receptor subtypes is being discovered (eg, multiple serotoniii receptor subtypes), all of them can be reduced to two simple classes called "superfamities."

The first superfamily mediates "slow neurolransmission" (Figure !land is named the ''seven transmembrane-G protein linked-seo ond messenger system" superfamily (Figure 2). Most neurotransmitter receptors for most psychotropic drugs belong to this class. Notable examples are subtypes of serotonin, norepinephrine, and dopamine receptors.

The other superfamily mediates "fast neurotransmission" (Figure 1) and is named the "ligand-gated ion channel" superfamily (Figures 3 and 4). An important example of this receptor is the GABA (Gamma-ainino-butyric acid) receptor linked both to benzodiazepine receptors and an inhibitory chloride ion channel (Figures 5 and 6).

Figure i, Some neurotransmitter signals are fast ("hare" neurons A and C) whereas other transmitter signals are slow ("tortoise" neuron 8). The neurotransmitter glutamate (neuron Ai is both fast and excitatory (+1 whereas ffie necirofransmitter GABA (neuron Ci is both fast and inhibitory (-). In contrast to the fast glutamate and GABA signals, neurotransmission following those neurotransmitters known as monoamines or neuropeptides tends to be slow ineuron B), and either excitatory (+) or inhibitory (-)."Fast" in this context is a few milliseconds whereas "slow" signals are many milliseconds or even several full seconds o! time. Slower acting neurotransmitters are sometimes called neuromodulators since they may modulate a different signal from another neurotransmitter In Figure 7, three neurons (A, B. and C) are all transmitting to a postsynaptic dendrite on the same neuron. If lhe slow signal from B is still presen! when a fas! signal from A or C arrives, the B signal will modulate the A or C signal. Thus, a long-ading neuromodulating signal of neuron B can set the tone of the postsynaptic neuron not only by a primary action of its own but also by modifying the action of neurons A and 8.

Figure i, Some neurotransmitter signals are fast ("hare" neurons A and C) whereas other transmitter signals are slow ("tortoise" neuron 8). The neurotransmitter glutamate (neuron Ai is both fast and excitatory (+1 whereas ffie necirofransmitter GABA (neuron Ci is both fast and inhibitory (-). In contrast to the fast glutamate and GABA signals, neurotransmission following those neurotransmitters known as monoamines or neuropeptides tends to be slow ineuron B), and either excitatory (+) or inhibitory (-).

"Fast" in this context is a few milliseconds whereas "slow" signals are many milliseconds or even several full seconds o! time. Slower acting neurotransmitters are sometimes called neuromodulators since they may modulate a different signal from another neurotransmitter In Figure 7, three neurons (A, B. and C) are all transmitting to a postsynaptic dendrite on the same neuron. If lhe slow signal from B is still presen! when a fas! signal from A or C arrives, the B signal will modulate the A or C signal. Thus, a long-ading neuromodulating signal of neuron B can set the tone of the postsynaptic neuron not only by a primary action of its own but also by modifying the action of neurons A and 8.

Figure 2. The functional outcome of neurotransmission is depicted here in ihe postsynaptic neuron. Neurotransmitter released from the presynaptic neuron is considered the first messenger. It binds to its receptor and the bound neurotransmitter causes an effector system to manufacture a second messenger That second messenger is inside the cell of the postsynaptic neuron. It is this second messenger which then goes on to create cellular actions and biological effects. Examples of this are to have the neuron begin to synthesize a chemical product, or to change its tiring rate.Thus, information in the presynaptic neuron is conveyed to the postsynaptic neuron by a chain of events, which take time to develop and are therefore "slow."

Figure 2. The functional outcome of neurotransmission is depicted here in ihe postsynaptic neuron. Neurotransmitter released from the presynaptic neuron is considered the first messenger. It binds to its receptor and the bound neurotransmitter causes an effector system to manufacture a second messenger That second messenger is inside the cell of the postsynaptic neuron. It is this second messenger which then goes on to create cellular actions and biological effects. Examples of this are to have the neuron begin to synthesize a chemical product, or to change its tiring rate.

Thus, information in the presynaptic neuron is conveyed to the postsynaptic neuron by a chain of events, which take time to develop and are therefore "slow."

Figure 3. This schematic shows a fast neurotransmitttng ion channel which is closed. It has a molecular gatekeeper shown here keeping !he channel dosed so that ions cannot gei into the cell.

Figure 3. This schematic shows a fast neurotransmitttng ion channel which is closed. It has a molecular gatekeeper shown here keeping !he channel dosed so that ions cannot gei into the cell.

Figure 4. Here the ion channel of the previous Figure 3 is rapidly opened. The gatekeeper has acted - perhaps upon instruction irom some neurotransmitter - to quickly open the channel and allow ions to trave/ into the cell.

Figure 4. Here the ion channel of the previous Figure 3 is rapidly opened. The gatekeeper has acted - perhaps upon instruction irom some neurotransmitter - to quickly open the channel and allow ions to trave/ into the cell.

Figure 5. Multiple modulalory sites nearby the fast neurotransmittmg GABA A receptor are shown here. These include not only the benzodiazepine (BZ) receptor, bul also sites for the convulsant drug picrotoxin, for the anticonvulsant barbiturate, and possibly for alcohol as well· These nearby receptors suggest how GABA may be involved in modulating such diverse physiological actions as anxiety, seizures, and even the actions of alcohol by actions on fas! neuroiransm/ssior).

Figure 5. Multiple modulalory sites nearby the fast neurotransmittmg GABA A receptor are shown here. These include not only the benzodiazepine (BZ) receptor, bul also sites for the convulsant drug picrotoxin, for the anticonvulsant barbiturate, and possibly for alcohol as well· These nearby receptors suggest how GABA may be involved in modulating such diverse physiological actions as anxiety, seizures, and even the actions of alcohol by actions on fas! neuroiransm/ssior).

Figure 6. GABA is lhe ligand which acts at the GABA A receptor site to participate in quickly opening the molecular gate lor an inhibitory chloride channel. Thus, when GABA alone binds to the GABA A receptor, it opens the chloride channel so that more chloride can now enter the cell and quickly cause inhibitory neurotransmission. Also shown is a benzodiazepine (BZ) ligand which is not binding to the benzodiazepine ieceplor in this exampfe.

Figure 6. GABA is lhe ligand which acts at the GABA A receptor site to participate in quickly opening the molecular gate lor an inhibitory chloride channel. Thus, when GABA alone binds to the GABA A receptor, it opens the chloride channel so that more chloride can now enter the cell and quickly cause inhibitory neurotransmission. Also shown is a benzodiazepine (BZ) ligand which is not binding to the benzodiazepine ieceplor in this exampfe.

10.3928/0048-5713-19960501-03

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