Download Receptors & Transmitters

Receptors & Transmitters
Basic Neuroscience NBL 120 (2007)
locks & keys
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)
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
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)
Small Molecules
Neuropeptides
Back to transmission…..
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
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
motoneurons (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)
Distribution: Norepinephrine (NE) 1%
locus coeruleus to
everywhere
attention, alertness
circadian rhythms
memory formation
mood
Distribrution: 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
Sythesis: 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)
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)
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
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
Binding sites on GABA receptors
 Opening of the
channel requires
GABA
 The other sites
are “allosteric” for
GABA binding
Congenital myesthenia
Single channel lifetime shortened
 - opening rate decreased
 - closing rate increased
(Wang et al, 1999)
Receptors  G Proteins  Effectors
Effectors
adenylyl cyclase
phospholipase C
cGMP phosphodiesterase
phosphoinositol-3-kinase
Metabotropic Receptor
G Protein
aka
GTP binding protein
heterotrimeric G protein
large G protein
Ca2+ channels
K+ channels
Na+ channels
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