Document 244312
Download
Report
Transcript Document 244312
DENT/OBHS 131
Neuroscience
Receptors & Transmitters
2009
Learning Objectives
Know what criteria are used to define a neurotransmitter
Recall the major different categories of transmitters
Know the names of the principle neurotransmitters in the
CNS (including: glutamate, GABA, acetylcholine,
norepinephrine, serotonin and dopamine)
Compare and contrast small the synthesis and action of
small molecular weight and peptide transmitters
Identify the brainstem nuclei associated with the biogenic
amine transmitters
Compare and contrast ligand-gated and G-protein coupled
receptors
You are a neurotransmitter if you….
are produced within a neuron, and are
present in the presynaptic terminal
are released during depolarization (action
potential-dependent manner)
act on receptors to cause a biological effect
have a mechanism of termination
More strictly, to be a transmitter..
a particular substance, when applied to the postsynaptic cell in quantities equal to that released by the
pre-synaptic cell, produces the same post-synaptic
response as does a pre-synaptic action potential
Learning Objective #2 & 3
Recall the major different categories of
transmitters
Know the names of the principle
neurotransmitters in the CNS (including:
glutamate, GABA, acetylcholine,
norepinephrine, serotonin and dopamine)
The keys
Small molecular weight:
Acetylcholine (ACh)
Amino acids:
Glutamate, GABA, glycine
Biogenic amines:
Catecholamines:
Dopamine, Norepinephrine (Epinephrine)
Indolamines:
Serotonin (5-HT), Histamine
Nucleotides
ATP , Adenosine
More keys...
Neuropeptides
Unconventional (what?)
(yes, I want to be a transmitter but I’m not
going to tell you exactly how)
Learning Objective #4
Compare and contrast small the
synthesis and action of small molecular
weight and peptide transmitters
Small Molecules
Neuropeptides
Back to transmission…..
Where are the transmitters?
Amino Acids
Glutamate
everywhere in CNS
major excitatory transmitter in CNS
most projection neurons in cortex use glutamate
GABA
everywhere in CNS
major inhibitory transmitter in CNS
found (not always) in local circuit neurons (interneurons)
Glycine
major inhibitory transmitter in brainstem and spinal cord
L-Glutamate
Synthesis and Degradation: GABA
The GABA Shunt
-ketoglutarate
glutamate
Kreb’s
Cycle
glutamic acid
decarboxylase
(GAD)
succinic semialdehyde
GABA
(release & uptake)
succinic acid
Distribution: Acetylcholine 5%
Ventral horn spinal
motor neurons (PNS)
to skeletal muscle
Brain stem motor nuclei
Striatum (local)
Septal nuclei to
hippocampus
Nucleus basalis to
cortex, amygdala,
thalamus
PNS - autonomic
Cognition - memory
Motor (striatum)
Learning Objective #5
Identify the brainstem nuclei associated
with the biogenic amine transmitters
Distribution: Norepinephrine (NE) 1%
Locus coeruleus to
everywhere
attention, alertness
circadian rhythms
memory formation
mood
Distribution: serotonin (5-HT) 1%
Rostral raphe nuclei
to nearly all regions
of the brain
Caudal raphe nuclei
to spinal cord
mood
sleep / wake cycles
pain modulation
Distribution: Dopamine 3%
Substantia nigra to
striatum
Ventral tegmentum to:
Amygdala, nucleus
Accumbens &
prefrontal cortex
Arcuate nucleus to
median eminence of
hypothalamus
movement
motivation
sex hormones
Synthesis: Dopamine
(these steps occur within the cytoplasm)
L-DOPA
COOH
+
CH2-CH-NH3
HO
O
H
tyrosine
hydroxylase
dopa
decarboxylase
H
COOH
HO
+
CH2-CH-NH3
Tyrosine
+
CH2-CH-NH3
HO
O
H
Dopamine
Synthesis: Norepinephrine
(these steps occur within the synaptic vesicle)
Norepinephrine
OH
+
HO
dopamine--hydroxylase O
(DBH)
H
H
+
CH2-CH-NH3
HO
O
H
Dopamine
CH-CH2-NH3
Transmitter termination
Clinical relevance:
Neurotransmitter transporters:
MAOs:
disease (epilepsy, ALS, Parkinson’s)
drug abuse (cocaine, amphetamine)
treatment (depression, OCD)
Learning Objective #6
Compare and contrast ligand-gated and
G-protein coupled receptors
Classes of Neurotransmitter
Receptors
Ionotropic Receptors
Ligand-gated ion channels
Fast synaptic transmission (1 ms)
Are closed (impermeable to ions) in absence of transmitter
Neurotransmitter binding opens receptor (direct)
Metabotropic Receptors
G-protein coupled receptors (GPCRs)
Slow onset and longer duration of effects (100 ms & longer)
Ligand binding activates GTP-binding proteins (indirect)
Ligand-gated / G-protein Coupled
Transmitter and receptor pairing
Both ionotropic and metabotropic receptors:
glutamate
acetylcholine
GABA
5HT (serotonin)
Just ionotropic:
glycine
Just metabotropic:
other biogenic amines (DA & NE)
Ligand-gated ion channels
Glutamate Receptor Subunits All Other Receptor Subunits
Each subunit
has multiple
membrane
spanning
domains
Glutamate: 3
All others: 4
Multimers
Glutamate: 4
All others: 5
Allosteric “other” binding sites
Congenital myasthenia
Single channel lifetime shortened
open slower & close faster
(Wang et al, 1999)
Structure of G-protein Coupled
Receptors
Single polypeptide with 7 TM domains (no subunits)
2nd & 3rd cytoplasmic loops plus part of the intracellular
tail bind to appropriate G protein
Agonist binding causes conformational
change that activates the G-protein
pertussis toxin
cholera
toxin
Direct modulation of Ca2+ channels
Modulation Through 2nd Messenger
Pathway
“Retro” transmitters
NO
endocannanbinoids
Definitions…
Agonist = activates (opens) the receptor when it binds
Antagonist = binds to the receptor and inhibits its function
different types
Allosteric modulators = act at a site different from agonist
Desensitization = response decrease although the agonist is
still present or repetitively applied
Ligand gated ion channels:
Gating = opening / closing of the channel
Kinetics = how long processes take
Affinity = tightness of the agonist binding
Efficacy = how readily the channel opens