1
Neurotransmitters, Neurotransmitter receptors and
their effects
No specific chapter reading for this.....stick to the slides!
We’re talking signals and what they mean to a neuron! What happens if we block signals?
2
General Sequence of Events at Chemical Synapses
• NTS synthesis and storage in presynaptic cell
• NTS release by exocytosis (Ca+
+ triggered event)• Diffusion across cleft• NTS reversibly binds to
receptors (LGC) and opens gates, allowing ion diffusion
• NTS removal from synapse (destruction, diffusion away)
• NTS reuptake by presynaptic cell for recycling
VOCC
Ca+2
3
NTS Action• NT diffuses across synaptic cleft to bind to
receptor (LGC) on postsynaptic membrane• Can generate an electric signal there
(EPSP’s or IPSP’s)• These are graded potentials (more
channels, more charge flux)• Effect depends which ions are allowed to
diffuse across membrane, how many and for how long. Effect depends on the selectivity of the channel.
• What if….. the LGC are…..– Na+ selective– K+ selective– Cl- selective
• What happens to the voltage on the postsynaptic cell? Is it an EPSP or an IPSP?
4
Neurotransmitters (NTs)• The substance must be present
within the presynaptic neuron• Must be released in response to
presynaptic depolarization, which must occur in a calcium dependent manner
• Specific receptors must be present on the postsynaptic cell
• NT must be removed to allow another cycle of NT release, binding and signal transmission
• Removal: reuptake by presynaptic nerve or glia or degradation by specific enzymes or a combination of these
5
Small molecule neurotransmitters• Acetylcholine (ACh)
– ACh (“cholinergic”)• Amino Acid Neurotransmitters
– Glutamate– Aspartate– GABA– Glycine
Catecholamines– Norepinephrine– Epinephrine
(“adrenergics”)– Dopamine
• Indoleamine– Serotonin
• Imidazolamine– Histamine
•Peptide Neurotransmitters (usually 3-30 aa’s long)Met-enkephalin, vasopressin (ADH), many others
www.brainexplorer.org/neurological_control/Neurological_Neurotransmitters.shtml
6
Acetylcholine• Used in NMJs• Sympathetic and
parasympathetic ganglia in PNS
• Acetylcholine esterase (AChE)
• “cholinergic” neurons have ChAT enzyme (choline acetyl transferase
http://abdellab.sunderland.ac.uk/Lectures/Nurses/cholinergic.html
7
Glutamate• Very important in CNS• Nearly all excitatory
neurons use it• Antagonists to Glutamate
receptor help stop neuronal death after stroke
• Too much- excitotoxicity due to unregulated calcium influx
• Too little, leads to psychosis (delusional, paranoid, lack of contact with reality
8
GABA and Glycine• Major inhibitory
neurotransmitter in CNS Decreased GABA-
seizures Anticonvulsants target
GABA receptors or act as GABA agonists
Valium- increases transmission of GABA at synapses
Benzodiazepines and ethanol trigger GABA receptors……use benzodiazepines during ethanol detox.
• Glycine- also inhibitory• Mostly in spinal cord and
brainstem motor neurons
http://pharma1.med.osaka-u.ac.jp/textbook/Anticonvulsants/GABA-syp.jpg
9
Catecholamines • Derived from amino acid
tyrosine - common precursor• Removed by reuptake into
terminals or surrounding glial cells via sodium dependent transporter
• Mono-amine oxidase (MAO) and catechol o-methyltransferase (COMT) degrade catecholamines
• Anti-anxiety agents- MAO-inhibitors
• DO NOT MIX SYMPATHOMIMETICS WITH MAOI’s!
phenylalaninePhenylalanine hydroxylase
DISORDER OF PHENYLALANINE METABOLISMPhenylketonuria (PKU)
• A genetic, autosomal recessive disorder (1:20,000 births)
• Lack of enzyme phenylalanine hydroxylase
• Inability to convert phenylalanine (aa) from the diet to tyrosine (aa)
• Accumulation of breakdown products of excess phenylalanine leads to neuronal degeneration, seizures, poor motor development and irreversible mental retardation in a developing child.
• Testing at birth in many states, also CA. Heel stick blood sample
• Prevented by dietary restriction on phenylalanine. No whole protein; source of all aa’s minus this one. At least through to adulthood, while nervous system is developing.
• Maternal PKU: what is it?• http://www.ddhealthinfo.org/ggrc/doc2.asp?ParentID=5166• http://ghr.nlm.nih.gov/condition=phenylketonuria
11
Dopamine• Parkinson’s Disease
(Parkinsonism)• Loss of dopamine from
neurons in substantia nigra of midbrain
• Resting tremor, “pill rolling”, bradykinesia, gait
• Treat with L-dopa. (Crosses BBB) or MAO inhibitors
• Side effects (hallucinations, motor)
The Case of the Frozen Addicts, by Langston, J. W
12
Serotonin• Synthesized from
tryptophan• Also known as 5-
hydroxytryptamine (5-HT)• SSRI’- selective serotonin
reuptake inhibitors are anti-depressant drugs
• Ecstasy causes more release!
• Mood elevator, “feel-good” neurotransmitter
13
14
Ionotropic Receptors Nicotinic AChR Serotonin
Glutamate GABAA Glycine
15
Metabotropic ReceptorsMetabotropic Receptors
Muscarinic Acetylcholine receptor Amanita muscaria Parasympathetic effectors stimulated Increased saliva, tears, diarrhea Antidote is atropine.
alpha and Beta-Adrenergic receptoralpha1-receptors:
bind G protein, activate inositol triphosphate and diacylglycerol as second messengers
alpha2 -receptors: bind the inhibitory G-protein, restrain the adenyl cylase system, reduce cAMP levels
beta-receptors: bind adenylate cyclase-stimulating G-protein, use cAMP as second messenger.
Some glutamate receptors, many, many others
16
MajorMajorIntracellularIntracellular
TransductionTransductionPathwaysPathwaysUsed by Used by
metabotropic metabotropic receptorsreceptors
cAMP Pathway IP3 Pathway
Signaling molecule
Cell surface receptor
G protein
Effector protein
Late effectors
Second messengercAMP IP3/DAG
Target protein
17
Signaling by GPCRs
18
Adenylate cyclase and guanylate cyclase– Make cyclic AMP and cyclic GMP
19
Protein kinase A dissociates
when activated by
cAMPRegulatory subunit
Catalytic subunit- Add/remove phosphates to/from enzymes to activate or deactivate them
20
Phosphatases remove phosphorylation; kinases
add
Better to think in terms of changes in activity Better to think in terms of changes in activity rather than activation (i.e. always basal state of rather than activation (i.e. always basal state of
activation)activation)
21
Gs
adrenergic receptor mechanismNE
AC
GTP R
C
CR
C CR
C
C
cAMP
P
PKA
cAMP
22
Inositol Trisphosphate & Inositol Trisphosphate & DAGDAG
23
Release of Intracellular Calcium
PKC
Aspects of IP3
signaling
Production of IP3
24
NT postsynaptic response and gene expression
• Open channels• Alter gene expression• Second messenger activation can lead to
phosphorylation of proteins that in turn regulate gene transcription
25
Drugs and Toxins
Spastic paralysis vs. flaccid paralysis
26
Sodium VGC Blockers• Lidocaine- used as
anesthesia• Tetrodotoxin-puffer
fish and newts (TTX)• Saxitoxin- caused by
red tide; dinoflagellate; accumulates in shellfish (SXT)
• Flaccid paralysis
27
Vesicle blockers• Clostridium botulinum:• It is a protease that
breaks down one of the fusion proteins (docking proteins that anchor the vesicle to the membrane)
• Inhibits neurotransmitter release
• Undercooked turkey; dented cans
• Flaccid paralysis• “BOTOX”
28
mACH-R blocker/ competitor
• Atropine• Flaccid paralysis• Smooth muscle,
heart, and glands
29
nACH-R blocker/ competitor
• Curare• From tree sap• Causes flaccid
paralysis• Large dose:
asphyxiation
30
AchE Blockers• Neostigmine• Physostigmine• Spastic paralysis• Myasthenia Gravis-
ptosis
31
AchE irreversible inhibitor
• DFP- di-isopropyl fluorophosphates
• Sarin• Spastic paralysis• Ventilator until AchE
turnover
32
Inhibitory Neuron Blockers
• Tetanus exotoxin • Blocks release of
inhibitory neurotransmitters
• Muscles can’t relax• Spastic paralysis• Opposing flexor and
extensor muscles contract
33
Spider Venom• Black widow: causes Ach
release– Lack of inhibitory
neurotransmitters– Spastic paralysis
• Brazilian Wandering Spider and Viagra?– Spider venom increases
NO release– Viagra blocks enzyme that
degrades NO– Most venomous of all
spiders/ more human deaths
Top Related