Download Synaptic Transmission

Synaptic Transmission
Kevin K. Caldwell, Ph.D.
2014 Neurochemistry and
Neuropharmacology
What is a synapse?
• a specialized junction that facilitates cell-tocell communication.
• The word commonly refers to a junction
between two neurons or between a neuron
and a non-neural cell, such as a muscle cell
or gland cell.
• Recently, the term has been applied to the
junction between a lymphocyte and an
antigen-presenting cell, which is referred to as
immunological synapse.
Early history
•
In the 2nd and 3rd centuries AD, Galen and his students
demonstrated that nerves arising in the brain and spinal cord were
necessary for muscle contraction
“All muscles require to receive a nerve from the brain or from
the spinal cord and this nerve is small to behold but by no
means slight in power.”
•
They proposed that these nerves carried “psychic pneuma”, which was formed in the
brain from the “vital pneuma” (originally proposed by Aristotle in the 4th century BC).
•
How was psychic pneuma in a nerve transferred to muscles? Three possible
mechanisms were considered by Galen:
1. The psychic pneuma flows along the nerve like a liquid.
2. The psychic pneuma in the brain pushes pneuma present in the nerves, releasing
some at the ends of the nerve.
3. There is a flow of “potency” through the psychic pneuma present in the nerves (similar
to idea of nerve conduction).
•
These ideas persisted for ~1500 years.
History of the understanding
of synaptic transmission
Studies aimed at addressing two issues led
to the development of our understanding of
synapses and synaptic transmission:
1. Neuron theory vs. reticular theory
2. Is synaptic transmission electrical or
chemical in nature?
Neuron theory vs. reticular
theory
• Neuron theory: neurons are discrete cells
which interact with, but are physically
separated from, other cells
• Reticular theory: the nervous system is a
complex syncytium consisting of a network
of cells which are not physically separate
from each other and which are in direct
cytoplasmic continuity
Timeline
•
•
•
•
1738: Swammerdam dispelled the idea that there was
continuity between a nerve ending and muscle and that
there was a direct flow of fluid from the nerve into the
muscle. He showed that muscles did not change in
volume during contraction.
1791: Luigi Galvani and the first documented
demonstration of synaptic transmission; “’animal
electricity”
1793: Alessandro Volta interpretation of L. Galvani’s
observation
1862-1863: Willy Kühne and Wilhelm Krause
independently describe the structure of the
neuromuscular junction; “currents of action”
Timeline
• 1877: du Bois-Reymond questions
whether transmission between nerve
and muscle is electrical or chemical in
nature.
• 1878: Bernard demonstrated that a
muscle could be caused to contract
independent of its nerve supply.
• 1886: Wilhelm His proposes that that
neurons are structurally independent
Timeline
• 1888: Santiago Ramón y Cajal observes
the termination of the axons of the stellate
cells of the cerebellum in pericellular
“baskets” around Purkinje cells.
Subsequently, Cajal was able to describe
multiple types of axonal endings in the
CNS, leading him to conclude that axon
terminals have distinct endings and that
neurons are not continuous with their
cellular targets
https://wiki.brown.edu/confluence/download/attachments/8082/Cowan_Briefhistory.pdf?version=1&modificationDate=11
56434029000
Timeline
• 1891: Waldeyer formulates the neuron
theory and introduces the term neuron
• 1897: Charles Sherrington (after
consulting with Arthur Woollgar Verrall)
coins the term synapse from the Greek
"syn-" ("together") and "haptein" ("to
clasp").
Timeline
• 1897: T. R. Elliott concludes that
adrenaline (epinephrine) is the transmitter
released by sympathetic postganglionic
fibers
• 1905: J. Newport Langley suggests that
transmission at the superior cervical
ganglion is mediated by “receptive”
substances on ganglion cells. This is the
basis for the concept of receptors.
Timeline
• 1914: Henry Dale concludes that
acetylcholine is likely to be a
neurotransmitter
• 1921: Otto Loewi describes “Vagastoff”
• 1934: Cajal’s last work, ¿Neuronismo o
Reticularismo?, which was later translated
into English as Neuron Theory or Reticular
Theory?, is the final, definitive argument
against the proposal that the nervous
system is a syncytium.
Timeline
• Mid 1950s: initial electron micrographs of
axon terminals and synapses
Two types of synapses:
1. Chemical synapse: a junction between a
neuron and another cell (neural or non-neural)
that allows for the nerve impulse to be
transmitted from the neuron to the other cell by
a chemical signal (a neurotransmitter).
2. Electrical synapse: the gap junction between
two apposed neurons that allows ions and small
molecules to pass from one neuron to the other.
Chemical synapses have a well-defined
directionality, while gap junctions are
bidirectional.
Chemical transmission
1.
2.
3.
4.
5.
Neurotransmitter synthesis
Neurotransmitter storage in secretory
vesicles
Release of neurotransmitter into the synapse
Postsynaptic receptors for the
neurotransmitter
A means for termination of the action of the
neurotransmitter
FIGURE 12-1: Depolarization opens voltage-sensitive Ca2+ channels in the presynaptic nerve
terminal (1). The influx of Ca2+ and the resulting high Ca2+ concentrations at active zones on the
plasmalemma trigger (2) the exocytosis of small synaptic vesicles that store neurotransmitter (NT) involved
in fast neurotransmission. Released neurotransmitter interacts with receptors in the postsynaptic membrane
that either couple directly with ion channels (3) or act through second messengers, such as (4) G-protein–
coupled receptors. Neurotransmitter receptors, also in the presynaptic nerve terminal membrane (5), either
inhibit or enhance exocytosis upon subsequent depolarization. Released neurotransmitter is inactivated by
reuptake into the nerve terminal by (6) a transport protein coupled to the Na+ gradient, for example,
dopamine, norepinephrine, glutamate and GABA; by (7) degradation (acetylcholine, peptides); or by (8)
uptake and metabolism by glial cells (glutamate). The synaptic vesicle membrane is recycled by (9) clathrinmediated endocytosis. Neuropeptides and proteins are stored in (10) larger, dense core granules within the
nerve terminal. These dense core granules are released from (11) sites distinct from active zones after
repetitive stimulation.
Copyright © 2012, American Society for Neurochemistry. Published by Elsevier Inc. All rights reserved.
Neurotransmitter / Drug
Receptors
The proposal that drugs interact with
the human body in specific, predictable
ways goes back to at least 1690.
“Did we but know the mechanical
affections of the particles of rhubarb,
hemlock, opium and a man…we should
be able to tell beforehand that rhubarb
will purge, hemlock kill and opium
make a man sleep…”
John Locke (1690)
The concept of the drug “receptor”:
Paul Ehrlich (1845-1915)
 in 1897 Erlich developed the
theory that 'side-chains' on
cells bound toxins.
He
proposed that these side
chains could be released into
the bloodstream, where they
would act as antitoxins or
antibodies.
 Ehrlich is credited with the
concept that that the drugreceptor interaction is similar
to a lock and its key.
http://www.nature.com/nrd/journal/v3/n9/images/nrd1498-f1.jpg
Paul Erlich’s depiction of the
“side-chain” – toxin interaction
Maehle et al 2002 Nature Rev Drug Disc
The concept of the drug “receptor”:
John Newport Langley (1852-1926)
 In 1905 Langley used
the term “receptive
substance” to explain
the actions of nicotine
and
curare
on
skeletal muscle, He
is credited with the
idea that drugs can
elicit an inhibitory
response.
http://www.historiadelamedicina.org/imagenes/langley.jpg
RECEPTOR
 A structure that recognizes endogenous or
exogenous compounds (ligands) with high
selectivity.
 Binding of the appropriate ligand to a receptor
initiates (or terminates) a physiologic process.
NOT ALL DRUG ACTIONS ARE
MEDIATED BY RECEPTORS
• Neutralization of stomach acid
with a base (antacid)
• osmotic diuretic action of
mannitol
References
•
•
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Bennett MR (1999) The early history of the synapse: from Plato to
Sherrington. Brain Res Bull. 50: 95-118.
http://ac.els-cdn.com/S0361923099000945/1-s2.0S0361923099000945main.pdf?_tid=f7e41563dd144c2bf8f63d703f2aff9a&acdnat=13
44474968_28f24c28526b14474ae9fbb2a23978a5
Cowan WM, Kandel ER. A Brief History of Synapses and Synaptic
Transmission. In Synapses; WM Cowan, TC Südhof, and CF
Stevens (Eds), The Johns Hopkins University Press: Baltimore,
2003; pp. 1-87.
https://wiki.brown.edu/confluence/download/attachments/8082/
Cowan_Briefhistory.pdf?version=1&modificationDate=1156434
029000
Hennig M. Modeling Synaptic Transmission.
http://homepages.inf.ed.ac.uk/mhennig/synaptic_transmission.
pdf