Receptors & Transmitters

DENT/OBHS 131Neuroscience

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 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

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: 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)

Learning Objective #5

Identify the brainstem nuclei associated with the biogenic amine transmitters

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)

Learning Objective #6

Compare and contrast ligand-gated and G-protein coupled receptors

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)

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)

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

Allosteric “other” binding sites

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

Direct modulation of Ca2+ channels

Modulation Through 2nd Messenger Pathway

“Retro” transmitters

NOendocannanbinoids

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