Neuroscience 106: Lecture 9 - Neurotransmitters and GPCRs

ANNOUNCEMENTS:

Midterm Covers Bear et al. Ch. 1 2 3 4 5 6 7.

Do the "Ion Problems" worksheet.

Take the practice exam before your discussion section meets.

TODAY'S LECTURE:

I. Neurotransmitters

A. A neurotransmitter is a chemical released by neurons in response to depolarization,

which produces an effect (usually a rapid effect) on another neuron.

B. Peptide neurotransmitters

1. They are chains of amino acids (which is the defining characteristic of a peptide).
2. They are synthesized solely in the soma of neurons.
3. They are released from secretory granules.

4. An example of some peptide neurotransmitters:

a. Opiate transmitters (they bind to the same receptors as morphine).

1. Enkephalins
2. Endorphins

b. Neuropeptide Y (NPY)
1. NPY is the most abundant peptide transmitter in the brain.
2. It is made up of 36 amino acids and thus is one of the larger peptide transmitters.
3. NPY stimulates feeding behavior in some areas of the brain.

C. Non-peptide neurotransmitters

1. Non-peptide neurotransmitters are smaller than peptide neurotransmitters.

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 2. Non-peptide neurotransmitters can be synthesized in the soma or in the terminal.

3. Some examples of non-peptide neurotransmitters...

a. Amino acid transmitters

1. Glutamate (the primary excitatory neurotransmitter in the mammalian brain).

2. gamma-amino-butyric-acid (GABA: the primary inhibitory transmitter found in the
mammalian brain).
3. Glycine (an inhibitory transmitter found mostly in the spinal cord).

b. Amines

1. Catecholamines
1. Dopamine (DA)
2. Norepinephrine (NE)
3. Epinephrine (E: which is also a hormone)

2. Acetylcholine (ACh: the neurotransmitter released at the neuromuscular junction

to produce muscle contractions [in contrast it inhibits heart rate]).

3. Serotonin (5-HT: which acts on 14 known receptors subtypes, the most of any
known neurotransmitter. It is considered to be an inhibitory neurotransmitter).

c. ATP (ATP is also used as a cellular source of energy).

d. Nitric oxide (NO: a gaseous molecule that can thus diffuse through the neural
membrane. It can be synthesized in the soma and diffuse back to a presynaptic
terminal.)

e. Endocannabinoids (they bind to the same receptors as cannabis).

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II. The common steps in synaptic transmission

A. Step one is the release of neurotransmitter from the presynaptic terminal.

B. Step two is the binding of the neurotransmitter to postsynaptic receptors.

1. There are two types of receptors, the ion channels and the metabotropic receptors.

a. Opening ion channels has an electrical effect (changes membrane potential).

b. Activation of metabotropic receptors (also known as G-protein linked receptors

[GPCRs] or second-messenger linked receptors) changes cell biochemistry.

Neurotransmitter can activate receptors that are ion channels or G-protein linked.

R = Receptor
G = G-protein
E = Effector ATP cAMP

a. Both receptor types have a binding site for the neurotransmitter.

b. Neurotransmitter binding to the receptor on the ion channel results in a brief change
in membrane potential by allowing the flux of ions.

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 c. Neurotransmitter (the first messenger) binding to the G-protein linked receptor (aka,
metabotropic receptor) activates a biochemical signaling cascade to produce a 2nd
biochemical messenger. Second messengers can have long lasting effects.

C. Step three is inactivation of the neurotransmitter.

1. Many neurotransmitter actions need to be brief. To make this possible inactivation

mechanisms are needed.

2. One mechanism of inactivation is simply the diffusion of the neurotransmitter away

from the synaptic cleft.

3. A second mechanism of inactivation is enzymatic degradation of the

neurotransmitter molecules.

4. A third mechanism of inactivation is via transporters that pump the neurotransmitter

away from the synaptic cleft. Transporters can pump the neurotransmitter back into the
presynaptic terminal (reuptake) or into astrocytes (a type of glial cell).

D. Step four is the reuptake of the synaptic vesicle. The synaptic vesicle is pinched back off
the membrane via endocytosis (the act of transmitter release is called exocytosis).

E. Step five is synthesis (or resynthesis) of neurotransmitter. Some neurotransmitters can

be resynthesized in the terminal and the neurotransmitter is then repackaged into
vesicles. These types of neurotransmitters are not depleted during periods of high activity
(while peptide transmitters are).

III. Drugs that affect neural activity

A. Drugs that affect neurotransmitter release.

1. e.g. Tetrodotoxin (TTX) blocks voltage-gated Na+ channels preventing action

potentials. Therefore action potential mediated neurotransmitter release is blocked.

2. e.g. Amphetamine increases the release of dopamine (DA) and norepinephrine (NE).

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 B. Drugs that affect receptors.
1. Agonists are drugs that bind to a receptor and mimic the effect of the endogenous
neurotransmitter (and they are frequently more specific than the endogenous
neurotransmitter). The endogenous transmitter itself is also an agonist at its receptor.

a. e.g. Morphine activates opiate receptors (mimicking enkephalins and

endorphins).

2. Antagonists are drugs that bind to receptors and block their activity.

a. e.g. Naloxone blocks opiate receptors.

b. e.g. Curare blocks nicotinic acetylcholine receptors (the acetylcholine receptor

subtype that is expressed in skeletal muscle) causing paralysis.

c. e.g. Atropine blocks muscarinic acetylcholine receptors, thereby preventing

slowing of heart rate.

d. e.g. Haloperidol blocks DA receptors. Therefore too much haloperidol produces

Parkinson-like symptoms.

C. Drugs that affect enzymatic degradation.

1. Nerve gas blocks acetylcholinesterase. Consequently there is an increase in the

synaptic concentration of ACh. Since ACh decreases heart rate, this stops the heart.
Atropine is an antidote for nerve gas.

D. Drugs that affect reuptake of neurotransmitter.

1. e.g. Cocaine blocks the reuptake of DA resulting in an increase in the concentration of

DA in the cleft.

E. Drugs that affect synthesis.

1. e.g. α-methyl-para-tyrosine (α-MPT) blocks the synthesis of DA, NE, and E.

IV. A bit more about synthesis

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 Retrograde direction (dynein)

kinesin
microtubules
dynein

Anterograde direction (AP & kinesin)

1. Transport from the soma to the terminal is anterograde transport.

2. Transport from the terminal to the soma is retrograde transport.

3. Anterograde transport...

a. Fast anterograde transport is about 1000 mm/day. Kinesin (which is a "motor")

walks along microtubules carrying the stuff to be transported.

b. Slow anterograde transport is ~ 10 mm/day. It is the bulk flow of cytoplasm down

the axon.

4. Fast retrograde transport is about 1000 mm/day. Dynein (which is a "motor") walks
along microtubules carrying the stuff to be transported.

B. Peptide synthesis is in the soma (rough ER to golgi where there is a budding off to form
secretory granules which are transported via fast anterograde transport to the terminals).

C. Synthesis of 3 non-peptide neurotransmitters (DA, NE, and E).

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 1. This is found in figures 6.12 and 6.13 in Bear et al. You need to know all of it, the
structures, enzymes, and all intermediates.

2. Dopamine (DA), norepinephrine (NE), and epinephrine (E) are called catacholamines
because they all contain the catechol nucleus:

Catechol nucleus

HO

HO R

3. Below is a partial reconstruction of figure 6.11. Synthesis of these neurotransmitters

starts with tyrosine which is an amino acid that comes from ingested protein.

Tyrosine (rate-limiting step)

(α-MPT looks like tyrosine, so it competes
Tyrosine hydroxylase (TH) with tyrosine for biding to tyrosine hydroxylase)

L-Dihydroxy-phenylalanine (L-DOPA)

Dopa decarboxylase

Dopamine (DA)

Dopamine ß-hydroxylase (DBH)

Norepinephrine (NE)

Phentolamine N-methyltransferase (PNMT)

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 Epinephrine

D. Why should you know the biosynthetic pathways?

1. It can help with identification of specific neurons in the brain that produce and release
a particular neurotransmitter. Antibodies to neurotransmitter synthesizing enzymes
can be used to visualize where neurons synthesizing a certain neurotransmitter are in
the brain. For example there are chemically segregated pathways for DA.

Frontal cortex = cognition

Caudate nucleus = motor control

Nucleus
accumbens =
“reward”

DA neurons from substantia nigra (SN)

DA neurons in ventral
tegmental area (VTA)

a. Substantia nigra (in the midbrain) contains DA neurons which project to the
caudate. The function of this circuit is planned motor activity. Increases in DA will
result in hyperactivity.

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 b. The ventral-tegmental area contains DA neurons that project to the nucleus
accumbens (involved in reward) and the cortex (involved in cognition).

2. There are also therapeutic reasons to know biosynthetic pathways.

a. Parkinson's disease is a motor disease that is neurochemical in origin. It is caused

by a progressive death of neurons in the substantia nigra projecting to the caudate.
A treatment is administration of the dopamine precursor L-DOPA.

b. An overdose of L-DOPA can produce schizophrenia like symptoms. A treatment for

schizophrenia is haloperidol (a DA receptor antagonist). An overdose of haloperidol
leads to Parkinson's like symptoms.

V. Metabotropic receptors (G-protein-coupled receptors, second-messenger-linked

receptors).

A. There are three components of metabotropic receptors (Figure 6.24).

1. The receptor itself.

2. The G-proteins which are associated with the receptor. When the receptor is activated
the α component of the G-protein breaks apart and interacts with effectors (as does
βγ).

3. The effector proteins.

B. For the short pathway (figure 6.25), the effectors open or close ion channels to change
membrane potential.

C. For the long pathway (figure 6.24 & 6.27) the effector is an enzyme which catalyzes
synthesis of some protein. This allows a cell surface signal (the neurotransmitter) to
affect the inside of the cell. An advantage of this system is amplification (Figure 6.30).
The process where one neurotransmitter molecule activates several G-proteins which
each activate several effector proteins, which each catalyze the synthesis of many
proteins.

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