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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)

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receptors transmitters

Receptors & Transmitters

Basic Neuroscience NBL 120 (2007)

you are a neurotransmitter if you
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
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
the keys
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
More keys...
  • Neuropeptides
  • Unconventional (what?)
    • (yes, I want to be a transmitter but I’m not going to tell you exactly how)
amino acids
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 gaba
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
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
Distribution: Norepinephrine (NE) 1%

locus coeruleus to everywhere

attention, alertness

circadian rhythms

memory formation

mood

distribrution serotonin 5 ht 1
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
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

H

COOH

+

CH2-CH-NH3

HO

CH2-CH-NH3

HO

OH

OH

COOH

+

+

HO

CH2-CH-NH3

Sythesis: Dopamine

(these steps occur within the cytoplasm)

L-DOPA

dopa decarboxylase

tyrosine

hydroxylase

Tyrosine

Dopamine

synthesis norepinephrine

H

+

CH2-CH-NH3

HO

+

OH

OH

CH-CH2-NH3

HO

OH

Synthesis: Norepinephrine

(these steps occur within the synaptic vesicle)

Norepinephrine

dopamine--hydroxylase

(DBH)

Dopamine

transmitter termination
Transmitter termination
  • Clinical relevance:
    • Neurotransmitter transporters:
    • MAOs:
      • disease (epilepsy, ALS, Parkinson’s)
      • drug abuse (cocaine, amphetamine)
      • treatment (depression, OCD)
classes of neurotransmitter 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)
definitions
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
transmitter and receptor pairing
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
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
Binding sites on GABA receptors
  • Opening of the channel requires GABA
  • The other sites are “allosteric” for GABA binding
congenital myesthenia
Congenital myesthenia
  • Single channel lifetime shortened

 - opening rate decreased

 - closing rate increased

(Wang et al, 1999)

receptors g proteins effectors
Receptors  G Proteins  Effectors

Effectors

adenylyl cyclase

phospholipase C

cGMP phosphodiesterase

phosphoinositol-3-kinase

Ca2+ channels

K+ channels

Na+ channels

Metabotropic Receptor

G Protein

aka

GTP binding protein

heterotrimeric G protein

large G protein

structure of g protein coupled receptors
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
Agonist binding causes conformational change that activates the G-protein

pertussis toxin

cholera

toxin

retro transmitters
“retro” transmitters
  • NO
  • endocannanbinoids
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