Post on 22-Dec-2015
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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 post-synaptic 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...
NeuropeptidesUnconventional (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
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
Synthesis and Degradation: GABASynthesis and
Degradation: GABA
Kreb’sCycle
-ketoglutarate glutamate
GABA(release & uptake)
The GABA Shunt
glutamic aciddecarboxylase (GAD)
succinic semialdehyde
succinic acid
Distribution: Acetylcholine 5%Distribution: Acetylcholine 5%
Ventral horn spinalmotor neurons (PNS)to skeletal muscleBrain stem motor nucleiStriatum (local)Septal nuclei to hippocampusNucleus basalis to cortex, amygdala, thalamusPNS - autonomic
Cognition - memoryMotor (striatum)
Locus coeruleus to everywhere
attention, alertness circadian rhythms memory formationmood
Distribution: Norepinephrine (NE) 1%
Rostral raphe nuclei to nearly all regions of the brainCaudal raphe nuclei to spinal cord
moodsleep / wake cyclespain modulation
Distribution: serotonin (5-HT) 1%
Substantia nigra tostriatumVentral tegmentum to:Amygdala, nucleus Accumbens & prefrontal cortexArcuate nucleus tomedian eminence ofhypothalamus
movementmotivationsex hormones
Distribution: Dopamine 3%
DopamineTyrosine
L-DOPA
tyrosinehydroxylase
dopa decarboxylase
HO CH2-CH-NH3
COOH+
HO CH2-CH-NH3
COOH
OH
+
HO
OH
CH2-CH-NH3
H+
(these steps occur within the cytoplasm)
Synthesis: Dopamine
dopamine--hydroxylase(DBH)
Dopamine
Norepinephrine
HO
OH
CH2-CH-NH3
H+
HO
OH
CH-CH2-NH3
OH+
(these steps occur within the synaptic vesicle)
Synthesis: Norepinephrine
Transmitter termination
Clinical relevance:Neurotransmitter transporters:MAOs:
disease (epilepsy, ALS, Parkinson’s)
drug abuse (cocaine, amphetamine) treatment (depression, OCD)
Classes of Neurotransmitter ReceptorsIonotropic 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)
Transmitter and receptor pairing
Both ionotropic and metabotropic receptors: glutamate acetylcholine GABA 5HT (serotonin)
Just ionotropic: glycine
Just metabotropic: other biogenic amines (DA & NE)
Each subunit has multiple membrane spanning domainsGlutamate: 3
All others: 4
MultimersGlutamate: 4
All others: 5
Glutamate Receptor Subunits
All Other Receptor Subunits
Ligand-gated ion channels
Congenital myasthenia
Single channel lifetime shortenedopen 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
cholera toxin
pertussis toxin
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