Synapses

The coordination of cellular activities in animals is usually considered to involve

an endocrine system: where the response is to hormones: chemicals secreted into the blood by endocrine glands and carried by the blood to the responding cell. [Link to introductory page on hormones]
a nervous system: response to electrical impulses passing from the central nervous system to muscles and glands.

But, in fact, coordination by the nervous system is also chemical. Most neurons achieve their effect by releasing chemicals, the neurotransmitters, on a receiving cell:

another neuron (a "postsynaptic" neuron)
a muscle cell
a gland cell

So the real distinction between nervous and endocrine coordination is that nervous coordination is

faster and
more localized

(Neurotransmitters are chemicals that act in a paracrine fashion.)

The junction between the axon terminals of a neuron and the receiving cell is called a synapse. (Synapses at muscle fibers are also called neuromuscular junctions or myoneural junctions.)

Action potentials travel down the axon of the neuron to its end(s), the axon terminal(s).
Each axon terminal is swollen forming a synaptic knob.
The synaptic knob is filled with membrane-bounded vesicles containing a neurotransmitter.
Arrival of an action potential at the synaptic knob opens Ca²⁺ channels in the plasma membrane.
The influx of Ca²⁺ triggers the exocytosis of some of the vesicles.
Their neurotransmitter is released into the synaptic cleft.
The neurotransmitter molecules bind to receptors on the postsynaptic membrane.
These receptors are ligand-gated ion channels.

Excitatory synapses

The neurotransmitter at excitatory synapses depolarizes the postsynaptic membrane (of a neuron in this diagram).

Example: acetylcholine (ACh)

Binding of acetylcholine to its receptors on the postsynaptic cell opens up ligand-gated sodium channels.
These allow an influx of Na⁺ ions, reducing the membrane potential.
This reduced membrane potential is called an excitatory postsynaptic potential or EPSP.
If depolarization of the postsynaptic membrane reaches threshold, an action potential is generated in the postsynaptic cell.

Inhibitory synapses

The neurotransmitter at inhibitory synapses hyperpolarizes the postsynaptic membrane.

Example: gamma aminobutyric acid (GABA) at certain synapses in the brain. Binding of GABA

to GABA_A receptors on the postsynaptic neuron opens up ligand-gated chloride (Cl^-) channels
to GABA_B receptors activates an internal G protein and a "second messenger" that leads to the opening of nearby potassium (K⁺) channels.

In both cases, the resulting facilitated diffusion of ions (chloride IN; potassium OUT) increases the membrane potential (to as much as -80 mv). This increased membrane potential is called an inhibitory postsynaptic potential (IPSP) because it counteracts any excitatory signals that may arrive at that neuron.

A hyperpolarized neuron appears to have an increased threshold. Actually, the threshold voltage (about -50 mv) has not changed. It is simply a question of whether the depolarization produced by excitatory synapses on the cell minus the hyperpolarizing effect of inhibitory synapses can reach this value or not.

Some neurotransmitters

Acetylcholine (ACh)

Widely used at synapses in the peripheral nervous system. Released at the terminals of

all motor neurons activating skeletal muscle. [Discussion]
all preganglionic neurons of the autonomic nervous system [Discussion]
the postganglionic neurons of the parasympathetic branch of the autonomic nervous system.

Also mediates transmission at some synapses in the central nervous system.

Amino acids

Glutamic acid (Glu); used at excitatory synapses in the central nervous system (CNS). Essential for long term potentiation (LTP), a form of memory.
Glycine (Gly); used at inhibitory synapses in the CNS.
Gamma aminobutyric acid (GABA); used at other inhibitory synapses in the CNS.

Catecholamines

Synthesized from tyrosine (Tyr)

Noradrenaline (also called norepinephrine). Released by postganglionic neurons of the sympathetic branch of the autonomic nervous system.
Dopamine. Used at certain synapses in the CNS.

Other monoamines

Serotonin. Synthesized from tryptophan (Trp).
Histamine

Both of these neurotransmitters are confined to synapses in the brain.

Peptides

A selection of seven of the 40 or more peptides that are suspected to serve as neurotransmitters in the brain. The first five also serve as hormones.

Vasopressin (ADH)
Oxytocin
Gonadotropin-releasing hormone (GnRH)
Angiotensin II
Cholecystokinin (CCK)
Two enkephalins
- Met-enkephalin (Tyr-Gly-Gly-Phe-Met)
- Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu)

Turning Synapses Off

Once its job is done, the neurotransmitter must be removed from the synaptic cleft to prepare the synapse for the arrival of the next action potential. Two methods are used:

Reuptake. The neurotransmitter is taken back into the synaptic knob of the presynaptic neuron by active transport. All the neurotransmitters except acetylcholine use this method.
Acetylcholine is removed from the synapse by enzymatic breakdown into inactive fragments. The enzyme used is acetylcholinesterase.
Nerve gases used in warfare (e.g., sarin) and the organophosphate insecticides (e.g., parathion) achieve their effects by inhibiting acetylcholinesterase thus allowing ACh to remain active. Atropine is used as an antidote because it blocks ACh receptors.

Drugs and Synapses

Many drugs that alter mental state achieve at least some of their effects by acting at synapses.

Link to discussion of drugs and the central nervous system.

GABA Receptors

The GABA_A receptor is a ligand-gated chloride channel. Activation of the receptors increases the influx of chloride (Cl^-) ions into the postsynaptic cell raising its membrane potential and thus inhibiting it.

A number of drugs bind to the GABA_A receptor. They bind at sites different from the spot where GABA itself binds, but increase the strength of GABA's binding to its site. Thus they enhance the inhibitory effect of GABA in the CNS.

These drugs include:

sedatives like phenobarbital
beverage alcohol (ethanol)
anti-anxiety drugs like Valium, Librium, Halcion (all members of a group called benzodiazepines)

In view of their common action, it is not surprising that they act additively; taken together (e.g., alcohol and Valium) these drugs can produce dangerous overdoses.

Catecholamine synapses

Many antidepressant drugs (the so-called tricyclic antidepressants like amitriptyline ["Elavil"]) interfere with the reuptake of noradrenaline and serotonin from their synapses and thus enhance their action at the synapse.

The popular antidepressant fluoxetine ("Prozac"), seems to block only the reuptake of serotonin.

Dopamine synapses

One class of dopamine receptor is bound by such drugs as chlorpromazine and haloperidol. Binding of these drugs leads to increased synthesis of dopamine at the synapse and eases some of the symptoms of schizophrenia.

Synapses blocking pain signals

The two enkephalins are released at synapses on neurons involved in transmitting pain signals back to the brain. The enkephalins hyperpolarize the postsynaptic membrane thus inhibiting it from transmitting these pain signals.

The ability to perceive pain is vital. However, faced with massive, chronic, intractable pain, it makes sense to have a system that decreases its own sensitivity . Enkephalin synapses provide this intrinsic pain suppressing system.

Opiates such as

heroin
morphine
codeine
methadone

bind these same receptors. This makes them excellent pain killers.

However, they are also highly addictive.

By binding to enkephalin receptors, they enhance the pain-killing effects of the enkephalins.
A homeostatic reduction in the sensitivity of these synapses compensates for continued exposure to opiates.
This produces tolerance, the need for higher doses to achieve the prior effect.
If use of the drug ceases, the now relatively insensitive synapses respond less well to the soothing effects of the enkephalins, and the painful symptoms of withdrawal are produced.

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2 November 1999