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NROC63H3 Lecture Notes - Neuropharmacology, Volt, Cardiac Muscle

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NROB60 Chapter 5
Imagine you stepped on a thumbtack and how it can be converted into a neural signal:
First, specialized ion channels of the sensory nerve endings allow positive charge to enter the axon
If this depolarization reaches threshold, then action potentials are generated
o Because the axonal membrane is excitable and has voltage-gated sodium channels, action potentials
can propagate without decrement up the long sensory nerves
For this information to be processed by the rest of the nervous system, it is necessary that these neural signals
be passed on to the other neurons that lead to a coordinated reflex response (e.g. lifting foot).
By the end of the 19th century, it was recognized that this transfer of information from one neuron to another occurs at
specialized sites of contact.
In 1897, Charles Sherrington gave these sites their names: synapse.
The process of information transfer at a synapse is called synaptic transmission
The physical nature of synaptic transmission was argued over and two prominent hypotheses arose:
One suggested it was electrical current flowing from one neuron to the next
o The existence of such electrical synapses was finally proven in 1959 by Edwin Furshpan and David
The other hypothesis suggested it was a chemical transfer of information
o This was also proven to be correct with solid support for the concept of chemical synapses by Otto
Loewi in 1921.
Types of Synapses
Electrical Synapses
o Electrical synapses are relatively simple in structure and function, and the allow the direct transfer of
ionic current from one cell to the next.
o They occur at specialized sites called gap junctions
The membrane of two cells is separated by only about 3nm and this narrow gap is spanned by
clusters of special proteins called connexins. Six of these combine to form a channel called a
connexon and two connexons combine to form a gap junction channel
It allows ions to pass directly from the cytoplasm of one cell to the cytoplasm of the other.
The pore is relatively large (1-2 nm) and is big enough for all the major cellular ions and many
small organic molecules to pass through
Most allow ionic current to pass equally well in both directions (unlike the majority of chemical
Cells connected by gap junctions are electrically coupled
o Transmission at the electrical synapses is very fast and, if the synapse is large, fail-safe.
An action potential in the presynaptic neuron can produce almost instantaneously, and action
potential in the postsynaptic neuron.
o Also occur in the vertebrae brain and is common in every part of the mammalian CNS
o When two neurons are electrically coupled, an action potential in the presynaptic neuron causes a small
amount of ionic current to flow across the gap junction channels into the other neuron
Causes a postsynaptic potential (PSP) in the second neuron
o Since most electrical synapses are bidirectional, when the second neuron generates an action potential,
it will in turn induce a PSP in the first neuron
o The PSP generated by a single electrical synapses in the mammalian brain is small and may not by
large enough to trigger an action potential in the postsynaptic cell
One neuron usually makes electrical synapses with many other neurons so several PSPs
occurring simultaneously may strongly excite a neuron (synaptic integration)
o The precise roles of electrical synapses vary from one brain region to another.
Chemical Synapses
Most synaptic transmission in the mature human nervous system is chemical
The presynaptic and postsynaptic membranes at chemical synapses are separated by a synaptic cleft that is
20 50 nm wide.
o It is filled with a matrix of fibrous extracellular proteins.
o One function is to make the pre- and post-synaptic membranes adhere to each other
o The presynaptic side of the synapse is usually an axon terminal and typically contains dozens of small
membrane-enclosed spheres called synaptic vesicles.
These vesicles store neurotransmitter, the chemical used to communicate with the postsynaptic
Many axon terminals also contain larger vesicles called secretory granules
They contain soluble protein that appears dark in the electron microscope and sometimes
called dense-core vesicles.
o Dense accumulations of protein adjacent to and within the membranes on either side of the synaptic
cleft are collectively called membrane differentiations.
On the presynaptic side, proteins jutting into the cytoplasm of the terminal along the intracellular
face of the membrane sometimes look like a field of tiny pyramids.
These are the actual sites of neurotransmitter release called active zones
Synaptic vesicles cluster adjacent to the active zones (Fig. 5.3)
o The protein thickly accumulated in and just under the postsynaptic membrane is called the
postsynaptic density.
It contains the neurotransmitter receptors, which convert the intercellular chemical signal into an
intracellular signal in the postsynaptic cell
o CNS Synapses
Different types of synapse may be distinguished by which part of the neuron is postsynaptic to
the axon terminal
If the postsynaptic membrane is on a dendrite, the synapse is said to be axodendritic
If the postsynaptic membrane is on the cell body, the synapse is said to be axosomatic.
If the postsynaptic membrane is on another axon, these synapses are called axoaxonic
In certain specialized neurons, dendirtes actually form synapses with one another. These
are called dendrodendritic synapses
CNS synapses may be further classified into two general categories based on the appearance of
their presynaptic and postsynaptic membrane differentiations
Synapses in which the membrane differentiation on the postsynaptic side is thick than on
the presynaptic side are called asymmetrical synapses or Gray’s type I synapses.
Those in which the membrane differentiations are of similar thickness are called
symmetrical synapses or Gray’s type II synapses
These structural differences predict functional differences.
o The Neuromuscular Junction
Chemical synapses also occur between the axons of motor neurons of the spinal cord and
skeletal muscle.
This is called a neuromuscular junction
Has many of the structural feathers of chemical synapses in the CNS
It is fast and reliable
o An action potential in the motor axon always causes an action potential in the
muscle cell it innervates
o Reliability is accounted for, in part, by structural specializations of the
neuromuscular junction
Its most important specialization is its size
o One of the largest synapses in the body
The presynaptic terminal also contains a large number of active zones
The post-synaptic membrane, motor end plate, contains a series of shallow folds
The presynaptic active zones are precisely aligned with these junctional folds, and the
postsynaptic membrane of the folds Is packed with neurotransmitter receptors
o It ensures that many neurotransmitter molecules are focally released onto a large
surface of chemically sensitive membrane
Principles of Chemical Synaptic Transmission
o Most neurotransmitters fall into one of three chemical categories:
Amino acids
o The amino acid and amine neurotransmitters are all small organic molecules containing at least one
nitrogen atom, and they are stored in and released from synaptic vesicles.
o Peptide neurotransmitters are large molecules stored in and released from secretory granules
Secretory granules and synaptic vesicles are frequently observed in the same axon terminals
o Different neurons in the brain release different neurotransmitters
Fast synaptic transmission at most CNS synapses is mediated by the amino acids glutamate
(Glu), gamma-aminobutyric acid (GABA) and glycine (Gly).
The amine acetylcholine (Ach) mediates fast synaptic transimission at all neuromuscular
junctions. Slower forms of synaptic transmission in the CNS and in the periphery are mediated by
transmitters from all three chemical categories.
Neurotransmitter Synthesis and Storage
o Chemical synaptic transmission requires that neurotransmitters be synthesized and ready for release.
o The synthesizing enzymes for both amino acid and amine neurotransmitters are transported to the axon
terminal, where they locally and rapidly direct transmitter synthesis.
o Once synthesized in the cytosol of the axon terminal, the amino acid and amin neurotransmitters must
be taken up by the synaptic vesicles.
Concentrating these neurotransmitters is the job of transporters
o Different mechanisms are used to synthesize and store peptides in secretory granules
This occurs in the rough ER
Generally, a long peptide synthesized in the rough ER is split in the Golgi apparatus, and of the
smaller peptide fragments is the active neurotransmitter.
Secretory granules containing the peptide neurotransmitter bud off the Golgi apparatus
and are carried to the axon terminal by axoplasmic transport
Neurotransmitter Release
o Neurotransmitter release is triggered by the arrival of an action potential in the axon terminal
o The depolarization of the terminal membrane causes voltage-gated calcium channels in the active
zones to open.
These membrane channels are very similar to the sodium channels
o There is a large inward driving force on Ca2+
o The resulting elevation in [Ca2+]I is the signal that causes neurotransmitter to be released from synaptic
o The vesicle releases their contents by a process called exocytosis.
o The membrane of the synaptic vesicle fuses to the presynaptic membrane at the active zone, allowing
the contents of the vesicle to spill out into the synaptic cleft (See Fig. 5.11.).
o Exocytosis is quick because Ca2+ enters at the active zone, precisely where synaptic vesicles are ready
and waiting to release their contents
o The precise mechanism by which [Ca2+]I stimulates exocytosis is poor understood
o The speed of neurotransmitter release suggests that the vesicles involved are those at ready “docked” at
the active zones.
Docking is believed to involved interactions between proteins in the synaptic vesicle membrane
and the active zone
In the presence of high [Ca2+]I, these proteins alter their conformation so that the lipid bilayers of
the vesicle and presynaptic membranes fuse, forming a pore that allows the neurotransmitter to
escape into the cleft.
The mouth of this exocytotic fusion pore continues to expand until the membrane of the vesicle is
fully incorporated into the presynaptic membrane
The vesicle membrane is later recovered by the process of endocytosis and the recycle vesicle
is refilled with neurotransmitter
o During periods of prolonged stimulation, vesicles are mobilized from a “reserve pool” that is bound to the
cytoskeletons of the axon terminal
The release of these vesicles from the cytoskeleton, and their docking to the active zone, is also
triggered by elevations of [Ca2+]i.
o Secretory Granules also release peptide neurotransmitters by exocytosis, in a calcium dependent
fashion, but not at the active zones