Receptors transmitters
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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

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Receptors transmitters

Receptors & Transmitters

Basic Neuroscience NBL 120 (2007)


Locks keys

locks & keys


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)


Small molecules

Small Molecules


Neuropeptides

Neuropeptides


Back to transmission

Back to transmission…..


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


Glutamate

glutamate


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


    Ligand gated g protein coupled

    Ligand-gated / G-protein Coupled


    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


    Direct modulation of ca 2 channels

    Direct modulation of Ca2+ channels


    Modulation through 2 nd messenger pathway

    Modulation Through 2nd Messenger Pathway


    Retro transmitters

    “retro” transmitters

    • NO

    • endocannanbinoids


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