Neuro: 1:00 - 2:00
Scribe: Strud Tutwiler
Monday, January 26, 2009
Proof: Ryan O’Neill
Dr. Lester
Receptors & Transmitters
Page 1 of 4
I. Receptors & Transmitters [S1]:
II. Learning Objectives [S2]
a. Going back to what Dr Baños lectured on. Review what has been seen in lab like transmitter systems and where
they are in the brain stem. Talk general role of transmitters: what they do, where we find them, how they are
synthesized, terminated, and what roles they play.
b. Compare and contrast major transmitters and receptors. Talk about ligand-gated receptors, nicotinicacetylcholine receptors, and g-protein coupled signaling.
c. Do need to know names of specific transmitters, but overall just know general information. Do not memorize all
transmitters, but know biogenic aiming and physiological role of small transmitters. We are expected to know
this list. The learning objective in green is not the main one, but just the first one talked about.
d. The different actions of two types of transmitters have: the small transmitter like Acetylcholine at the
neuromuscular junction or the peptides (100 different peptide transmitters).
e. Peptides function fundamentally different from the small transmitters.
III. You are a neurotransmitter if you… [S3]
a. Here are criteria to define a transmitter in presynaptic terminal. Largely in vesicles and released in action
potential-dependent manner (synaptic transmission).
b. Largely act on ligand-gated or g-protein receptors on cell surface. Have to have specific mechanism of
termination.
IV. More strictly, to be a transmitter… [S4]
a. There was an experiment to show that a chemical is released when vagus nerve is stimulated to the heart.
Stimulated vagus nerve and collected Acetylcholine, and put it another heart to show slowing of heart rate. This
was the first evidence that there was a chemical released from a nerve. Other transmitters were isolated later.
b. This figure shows effect of one vesicle on muscle. It causes a very small amount of excitatory postsynaptic
potential. If you put Acetylcholine on the small muscle, you get the same effect. This is what a transmitter is. If
it has same effect and duration, its mechanism and termination is probably the same.
V. Learning Objectives 2 & 3 [S5]
a. Split down transmitters into three different categories: small MW (with subcategories), peptides, and others.
VI. The Keys [S6-7]
a. Acetylcholine is transmitter in NMJ in all autonomic ganglion synapses (sympathetic or parasympathetic) and
signaling within the brain.
b. Amino acids are involved in synaptic transmission. Glutamate is excitatory, and GABA and glycine are
inhibitory.
c. Dopamine, Norepinephrine (noradrenaline), and serotonin are important. Should know where they are in the
brain stem, and what they are acting. He also mentioned histamine, as it has an effect on the brain, but said it
was not as important. Histamine is distributed diffusely.
d. ATP can be packed in vesicles and released. ATP has an action on purinergic receptors and its breakdown
product adenosine, also has an effect. Know all of these.
e. Neuropeptides: enkephalins, substance p, CCK (important for feeding behavior). They will be discussed later in
semester.
VII. Learning Objective 4 [S8]
a. Two important differences in comparing small transmitters to peptides. First is how and where they are
synthesized. Second is how they function generally at the synapse.
VIII. Small Molecules [S9]
a. Generalized example of a neuron. The figure shows location of synthesis of small MW transmitters. They are
synthesized locally in the terminal. Proteins are made in the cell body and transported down. Synthetic
enzymes are made in the cell body and moved to the terminal for synthesis.
b. Ex. Enzymes that locally synthesize Acetylcholine. When Acetylcholine is broken down, choline is taken up
and reused again, so it can be a limiting factor.
c. General rule: all of transmitters and made and then packaged into vesicles. Norepinephrine is an exception.
Norepinephrine is synthesized within vesicle itself. Know this.
IX. Neuropeptides [S10]
a. Proteins are synthesized and packaged into vesicles; then taken down terminal by axonal transport.
b. EM pictures of presynaptic vesicles come in two types. Small MW transmitters are packaged in clear vesicles
docked close to release sites.
c. Electron dense vesicles in EM have peptides in them. They are further back than clear vesicles.
X. Back to transmission… [S11]
a. Clear synaptic vesicles contain Acetylcholine, glutamine, or GABA all packaged at synapse ready to be realized.
This is a very rapid and efficient process. Diffuse very quickly across synapse to bind to receptors.
Neuro: 1:00 - 2:00
Scribe: Strud Tutwiler
Monday, January 26, 2009
Proof: Ryan O’Neill
Dr. Lester
Receptors & Transmitters
Page 2 of 4
b. Peptides on the other hand, have more profuse and slow action. In general, their post-synaptic binding to Gproteins is slower and their release is slower.
c. Ca entry into presynaptic terminal for release with a Ca sensor is important. A single action potential comes
down, low frequency, and a vesicle is released. Ca goes high for a short time, then is buffered (normally does
not spread far in terminal).
d. Ca can spread far with high frequency input. This is what the dense-core peptide vesicle depend on, because
normally Ca does not get high enough to activate the sensors on the dense-core vesicles. Higher frequency is
required for higher Calcium concentrations.
e. The calcium sensor for the dense-core vesicles has a higher sensitivity for calcium.
f. These vesicles might be released epi-synaptic or peri-synaptic. Transmitter might be able to act at more of a
distance. If peptidases are present in the CSF, the transmitter will be chewed up. This will have a breakdown
hydrolysis to keep it from acting too far though.
g. Overall, neuropeptides are thought to have a more diffuse/distant effect than the other transmitters.
h. Think of peptide and small MW transmitters as being distinct in both how they are synthesized, packaged,
released, and postsynaptic action.
i. Remember that small MW peptides are FAST, and neuropeptides are SLOW.
XI. Where are the transmitters? [S12]
XII. Amino Acids [S13]
a. Probably no neurons in the brain do not use glutamate or are not acted upon by glutamate. Glutamate is used
for fast excitation in CNS. Used in cortical cells and in brain stem.
b. Major inhibitory transmitters: GABA is found in brain, while glycine is usually found in the brain stem and spinal
cord. Know these locations for inhibitors, but they do overlap some.
XIII. L-Glutamate [S14]
a. Local synthesis and recycling of glutamate and GABA. Glutamate synthesis, a localized process, involves
glutamate taken up by astrocytes and rapidly broken down into glutamine.
b. If glutamate is broken down rapidly, there is a gradient for glutamate to enter astrocytes.
c. Glutamine is taken back into the presynaptic terminal and converted into Glutamate.
d. Important: Glutamate is a major part of metabolic cycles. It has its own loop with an astrolytic presynaptic
shuttle. If all neurons use glutamate, want to degrade it very quickly (toxic).
XIV.
Synthesis and Degradation: GABA [S15]
a. GABA comes off the Kreb Cycle, and Glutamate source is not the same source as the synthetic glutamine to
glutamate cycle in neurons/glial cells. This is completely separate pathways.
b. Can tell a GABA neuron because it expresses the enzyme glutamic acid decarboxylase (GAD). GAD is GABA’s
major synthetic enzyme.
c. If you stain neurons, and you see ones with GAD, then they release GABA. Most of the others release
glutamate. You can identify these neurons.
d. It is a shunt out of the Kreb Cycle; synthesized, broken down, and returned to the Kreb Cycle.
XV. Distribution: Acetylcholine 5% [S16]
a. Be able to associate transmitters with different nuclei and where they are in the brain stem.
b. Acetylcholine is found in nucleus basalis (known to degenerate in Alzheimer’s resulting in loss of Acetylcholine).
c. Figure shows nucleus basalis. To find it on a coronal section, look at the coronal section with the Anterior
Commissure (connects the two temporal lobes). The nucleus basalis is the grey structure directly under the
Anterior Commissure.
d. This provides excitation/modulation to the cortex. Other septal nuclei project to the limbic system, specifically
the hippocampus. Acetylcholine is needed to store new memories. Limbic system controls memory and
cognition.
e. Clinically, the drugs used to treat Alzheimer’s are cholinesterase inhibitors, to enhance the action of
Acetylcholine.
f. There are individual cholinergic cells in the striatum that play a role with respect to locomotion along with
dopamine.
g. Nuclei in brainstem sending descending projections work with Acetylcholine as well (vagal nucleus, CN X).
Spinal cord (motor neurons) are cholinergic in nature.
XVI.
Learning Objective 5 [S17]
XVII. Distribution: Norepinephrine (NE) 1% [S18]
a. NE is located in the locus coeruleus (do not worry about spelling). Locus coeruleus is pigmented structure in
the pons (alien eyes). It is a long thin nucleus that expands most of the length of the pons.
b. There are a few scattered nuclei in the brain that synthesize NE, but this is the major supply of NE to the brain
and spinal cord.
Neuro: 1:00 - 2:00
Scribe: Strud Tutwiler
Monday, January 26, 2009
Proof: Ryan O’Neill
Dr. Lester
Receptors & Transmitters
Page 3 of 4
c. Attention, alertness, memory, mood are several of the jobs of the locus coeruleus. These cells can project all
the way through your brain and alter synapses across the whole cortex. They have generalized diffuse,
modulator roles.
d. Raphe nuclei are series of nuclei that lay at the midline and run the entire brain. Separated into rostral and
caudal. The caudal ones project to spinal cord and rostral do everything else.
XVIII. Distribution: Serotonin (5-HT) 1% [S19]
a. Serotonin and NE projections to the spinal cord are important for pain modulation.
b. Serotonin selective reuptake inhibitors (Prozac) modulate one’s mood.
c. Serotonin, NE, and Acetylcholine play a reciprocal role in sleep/wake cycles. Control mechanisms turn each
other off to control REM sleep, non-REM sleep, when you are awake, etc.
XIX.
Distribution: Dopamine 3% [S20]
a. Two of the main dopaminergic nuclei are the VTA (ventral tegmentum area) and substantia nigra. The nucleus
accumbens is one of their projection sites. The nucleus accumbens is known as the ventral striatum in the
gross lab. It is where the caudate and the putamen nuclei meet.
b. This emphasizes that the caudate and putamen have similar functions, and the caudate putamen of the dorsal
striatum receive dopaminergic projections from the substantia nigra. The ventral striatum receive dopaminergic
projections from the VTA.
c. Have massive projections to the dorsal striatum, the caudate putamen complex, and to the nucleus accumbens,
which lies at the ventral aspect of the caudate putamen where they meet.
d. To find it, look through anterior coronal sections at the caudate putamen, where the internal capsule is not quite
cutting them both in half. The internal capsule is found under the nucleus accumbens.
XX. Synthesis: Dopamine [S21]
a. Loss of caudate correlates with Huntingdon’s Disease. In Parkinson’s disease, you lose your input in the
substantia nigra. These, motor coordination, VTA, nucleus accumbens, and addiction are associate with
dopamine.
b. The synthesis of dopamine form part of the clinical analysis of Parkinson’s disease and how it is treated.
c. L-DOPA is a precursor of dopamine; it was the first treatment for Parkinson’s disease. It was used to wake up
patients.
d. All of this happens locally because it is a small MW transmitter in the terminal.
XXI.
Synthesis: Norepinephrine [S22]
a. Dopamine is transported into the vesicles. A dopaminergic neuron is will keep dopamine, but a neuron in the
locus coeruleus contains Dopamine B Hydroxylase that turns dopamine into NE.
b. Not much different between a dopaminergic neuron and a Norepinephrine neuron.
XXII. Transmitter Termination [S23]
a. Termination: hydrolysis of Acetylcholine at the NMJ and CNS. The major termination mechanism for small MW
is uptake. NE and Dopamine are reuptaken.
b. Monoamine oxidase (MAO) inhibitors, inside cells, break down NE and dopamine. These are clinically useful.
The first antidepressants were MAOs, but recently switched to uptake inhibitors. Either way, doctors were trying
to increase serotonin or NE.
c. Maybe in Parkinson’s, there are chemicals (pesticides) that can be transmitted through the dopamine
transporter. These pesticides along with a genetic predisposition can cause death.
d. Cocaine and amphetamine act on dopamine and NE uptake and transporter. Cocaine inhibitors NE uptake and
causes a boost in dopamine levels.
e. Treatment: depression, OCD (Ritalin acts on dopamine uptake). There are many implications for dysfunctions
and diseases of these transport systems. Cholinesterase inhibitors are used for cognitive decline and
myasthenia.
XXIII. Learning Objective 6 [S24]
a. Talk about receptors and g-proteins.
XXIV. Classes of Neurotransmitter Receptors [S25]
a. Small MW transmitters tend to be fast; peptide transmitters need to be slow. They cannot be matched with
receptors. Both transmitters act on ligand-gated and g-proteins receptors.
b. Ligand-gated ion channel or ionotropic receptors are fast.
c. Metabotropic Receptors (G-protein) are at least a magnitude of order slower. If ionotropic receptors are one
millisecond, then these are going to be 10-100 milliseconds.
d. Because there is a g-protein intermediate between receptors and ultimate effectors system, we can get
amplification and prolonged duration.
XXV. Ligand-gated / G-protein Coupled [S26]
a. Binding of ligand receptor, opens/closes channel.
Neuro: 1:00 - 2:00
Scribe: Strud Tutwiler
Monday, January 26, 2009
Proof: Ryan O’Neill
Dr. Lester
Receptors & Transmitters
Page 4 of 4
b. Intrinsic ion channel. A receptor activates a G-protein to move along and activates an ion channel.
c. Advantage of G-proteins is they can open or close ion channels. Disadvantage: Slower
d. Potassium channels are opened by G-proteins. Potassium equilibrium potential is around resting membrane
potential. If potassium channels are closed, depolarization occurs. If K channels are opened, hyperpolarization
occurs. Dopamine, serotonin, and NE just act to modulate K channels and control excitability.
XXVI. Transmitter and Receptor Pairing [S27]
a. Small MW proteins have both ionotropic and metabotropic receptors.
b. Some of the biogenic amines are just metabotropic, while glycine is only ionotropic. Mixed actions are
generalizations.
XXVII. Ligand-gated Ion Channels [S28]
a. Not as important. Just there are two main families of ligand-gated ion channels: glutamate and rest (nicotinic,
serotonin, GABA, acetylcholine, etc).
XXVIII. Allosteric “other” binding sites [S29]
a. Many drugs have modulator sites. Important for anesthetics. Two important sites are barbiturates sites and
benzodiazepine (BZ) site. Both provide prolonged activation for GABA, increased inhibition, sleepiness,
sedation, and anesthesia.
b. This is also important for epilepsy.
XXIX. Congenital Myasthenia [S30]
a. Many of the proteins can be altered genetically in the way they function. Many mutations at ligand-gated ion
channels and K channels cause them not to function correctly.
b. Myasthenia gravis = autoimmune disease to breakdown and crosslink nicotinic receptors (limited).
c. Can alter way receptors open and close genetically. A mutation can cause the channel to open and close too
quickly at the NMJ causing weakness.
d. This is a response at NMJ of a normal person on top. The patient’s response is weak. Everyone has mutations
in channels and most of them are inert.
XXX. Structure of G-protein Coupled Receptors [S31]
a. There are seven membrane-spanning domains or families in G-protein coupled receptors. They have a big
intracellular tail that part that interacts with the G-proteins.
XXXI. Agonist Binding Causes Conformational Change that Activates the G-protein [S32]
a. Certain toxins, pertussis toxin and cholera toxin, can disturb the function of the G-protein coupled signaling.
b. Pertussis toxin can prevent the interaction between the receptor and the G-protein. This stops the signaling.
c. Cholera toxin has permanent inactivation effect on gs alpha. Still get cAMP and stimulation of effectors.
XXXII. Direct Modulation of Ca channels [S33]
a. In the nervous system, G-proteins convey signaling at terminals. Some auto feedback and cross feedback
occurs to the terminals. One of the major ways that these transmitters interact presynaptically is to control the
Calcium in the presynaptic terminal.
b. The major presynaptic form of modulation in the CNS is to the do this depressed synaptic transmission. Most of
the biogenic amines, NE, GABA receptors, glutamate receptors can do this.
c. This is a common effect to depress (negative feedback loop) to keep it from getting overactive.
XXXIII. Modulation through second messenger pathway [S34]
a. The direct breakdown products of the G-protein (alpha, beta, or gamma subunit) can affect the calcium channel.
b. Second messengers can also have an impact on calcium channels. Can have direct or indirect (enzymatic
systems) effect on channels.
XXXIV. “Retro” transmitters [S35]
a. NO = nitric oxide is produced in neurons by nitric oxide synthase. NO will relax blood vessels by diffusing
readily. It has an action we can mimic.
b. Endocannanbinoids = THC the active ingredient in marijuana. It contains endogenous ligands. Seem to act in a
retrograde fashion. Can go back after released to act on presynaptic terminals to dampen things down.
c. These are the not well-defined transmitters.
XXXV. Definitions… [S36]
a. Agonist vs. Antagonist.
[End 51:13 min]