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Neurotransmitters, Neurotransmitter receptors and

their effects

No specific chapter reading for this.....stick to the slides!

We’re talking signals and what they mean to a neuron! What happens if we block signals?

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General Sequence of Events at Chemical Synapses

• NTS synthesis and storage in presynaptic cell

• NTS release by exocytosis (Ca+

+ triggered event)• Diffusion across cleft• NTS reversibly binds to

receptors (LGC) and opens gates, allowing ion diffusion

• NTS removal from synapse (destruction, diffusion away)

• NTS reuptake by presynaptic cell for recycling

VOCC

Ca+2

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NTS Action• NT diffuses across synaptic cleft to bind to

receptor (LGC) on postsynaptic membrane• Can generate an electric signal there

(EPSP’s or IPSP’s)• These are graded potentials (more

channels, more charge flux)• Effect depends which ions are allowed to

diffuse across membrane, how many and for how long. Effect depends on the selectivity of the channel.

• What if….. the LGC are…..– Na+ selective– K+ selective– Cl- selective

• What happens to the voltage on the postsynaptic cell? Is it an EPSP or an IPSP?

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Neurotransmitters (NTs)• The substance must be present

within the presynaptic neuron• Must be released in response to

presynaptic depolarization, which must occur in a calcium dependent manner

• Specific receptors must be present on the postsynaptic cell

• NT must be removed to allow another cycle of NT release, binding and signal transmission

• Removal: reuptake by presynaptic nerve or glia or degradation by specific enzymes or a combination of these

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Small molecule neurotransmitters• Acetylcholine (ACh)

– ACh (“cholinergic”)• Amino Acid Neurotransmitters

– Glutamate– Aspartate– GABA– Glycine

Catecholamines– Norepinephrine– Epinephrine

(“adrenergics”)– Dopamine

• Indoleamine– Serotonin

• Imidazolamine– Histamine

•Peptide Neurotransmitters (usually 3-30 aa’s long)Met-enkephalin, vasopressin (ADH), many others

www.brainexplorer.org/neurological_control/Neurological_Neurotransmitters.shtml

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Acetylcholine• Used in NMJs• Sympathetic and

parasympathetic ganglia in PNS

• Acetylcholine esterase (AChE)

• “cholinergic” neurons have ChAT enzyme (choline acetyl transferase

http://abdellab.sunderland.ac.uk/Lectures/Nurses/cholinergic.html

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Glutamate• Very important in CNS• Nearly all excitatory

neurons use it• Antagonists to Glutamate

receptor help stop neuronal death after stroke

• Too much- excitotoxicity due to unregulated calcium influx

• Too little, leads to psychosis (delusional, paranoid, lack of contact with reality

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GABA and Glycine• Major inhibitory

neurotransmitter in CNS Decreased GABA-

seizures Anticonvulsants target

GABA receptors or act as GABA agonists

Valium- increases transmission of GABA at synapses

Benzodiazepines and ethanol trigger GABA receptors……use benzodiazepines during ethanol detox.

• Glycine- also inhibitory• Mostly in spinal cord and

brainstem motor neurons

http://pharma1.med.osaka-u.ac.jp/textbook/Anticonvulsants/GABA-syp.jpg

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Catecholamines • Derived from amino acid

tyrosine - common precursor• Removed by reuptake into

terminals or surrounding glial cells via sodium dependent transporter

• Mono-amine oxidase (MAO) and catechol o-methyltransferase (COMT) degrade catecholamines

• Anti-anxiety agents- MAO-inhibitors

• DO NOT MIX SYMPATHOMIMETICS WITH MAOI’s!

phenylalaninePhenylalanine hydroxylase

DISORDER OF PHENYLALANINE METABOLISMPhenylketonuria (PKU)

• A genetic, autosomal recessive disorder (1:20,000 births)

• Lack of enzyme phenylalanine hydroxylase

• Inability to convert phenylalanine (aa) from the diet to tyrosine (aa)

• Accumulation of breakdown products of excess phenylalanine leads to neuronal degeneration, seizures, poor motor development and irreversible mental retardation in a developing child.

• Testing at birth in many states, also CA. Heel stick blood sample

• Prevented by dietary restriction on phenylalanine. No whole protein; source of all aa’s minus this one. At least through to adulthood, while nervous system is developing.

• Maternal PKU: what is it?• http://www.ddhealthinfo.org/ggrc/doc2.asp?ParentID=5166• http://ghr.nlm.nih.gov/condition=phenylketonuria

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Dopamine• Parkinson’s Disease

(Parkinsonism)• Loss of dopamine from

neurons in substantia nigra of midbrain

• Resting tremor, “pill rolling”, bradykinesia, gait

• Treat with L-dopa. (Crosses BBB) or MAO inhibitors

• Side effects (hallucinations, motor)

The Case of the Frozen Addicts, by Langston, J. W

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Serotonin• Synthesized from

tryptophan• Also known as 5-

hydroxytryptamine (5-HT)• SSRI’- selective serotonin

reuptake inhibitors are anti-depressant drugs

• Ecstasy causes more release!

• Mood elevator, “feel-good” neurotransmitter

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Ionotropic Receptors Nicotinic AChR Serotonin

Glutamate GABAA Glycine

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Metabotropic ReceptorsMetabotropic Receptors

Muscarinic Acetylcholine receptor Amanita muscaria Parasympathetic effectors stimulated Increased saliva, tears, diarrhea Antidote is atropine.

alpha and Beta-Adrenergic receptoralpha1-receptors:

bind G protein, activate inositol triphosphate and diacylglycerol as second messengers

alpha2 -receptors: bind the inhibitory G-protein, restrain the adenyl cylase system, reduce cAMP levels

beta-receptors: bind adenylate cyclase-stimulating G-protein, use cAMP as second messenger.

Some glutamate receptors, many, many others

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MajorMajorIntracellularIntracellular

TransductionTransductionPathwaysPathwaysUsed by Used by

metabotropic metabotropic receptorsreceptors

cAMP Pathway IP3 Pathway

Signaling molecule

Cell surface receptor

G protein

Effector protein

Late effectors

Second messengercAMP IP3/DAG

Target protein

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Signaling by GPCRs

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Adenylate cyclase and guanylate cyclase– Make cyclic AMP and cyclic GMP

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Protein kinase A dissociates

when activated by

cAMPRegulatory subunit

Catalytic subunit- Add/remove phosphates to/from enzymes to activate or deactivate them

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Phosphatases remove phosphorylation; kinases

add

Better to think in terms of changes in activity Better to think in terms of changes in activity rather than activation (i.e. always basal state of rather than activation (i.e. always basal state of

activation)activation)

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Gs

adrenergic receptor mechanismNE

AC

GTP R

C

CR

C CR

C

C

cAMP

P

PKA

cAMP

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Inositol Trisphosphate & Inositol Trisphosphate & DAGDAG

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Release of Intracellular Calcium

PKC

Aspects of IP3

signaling

Production of IP3

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NT postsynaptic response and gene expression

• Open channels• Alter gene expression• Second messenger activation can lead to

phosphorylation of proteins that in turn regulate gene transcription

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Drugs and Toxins

Spastic paralysis vs. flaccid paralysis

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Sodium VGC Blockers• Lidocaine- used as

anesthesia• Tetrodotoxin-puffer

fish and newts (TTX)• Saxitoxin- caused by

red tide; dinoflagellate; accumulates in shellfish (SXT)

• Flaccid paralysis

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Vesicle blockers• Clostridium botulinum:• It is a protease that

breaks down one of the fusion proteins (docking proteins that anchor the vesicle to the membrane)

• Inhibits neurotransmitter release

• Undercooked turkey; dented cans

• Flaccid paralysis• “BOTOX”

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mACH-R blocker/ competitor

• Atropine• Flaccid paralysis• Smooth muscle,

heart, and glands

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nACH-R blocker/ competitor

• Curare• From tree sap• Causes flaccid

paralysis• Large dose:

asphyxiation

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AchE Blockers• Neostigmine• Physostigmine• Spastic paralysis• Myasthenia Gravis-

ptosis

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AchE irreversible inhibitor

• DFP- di-isopropyl fluorophosphates

• Sarin• Spastic paralysis• Ventilator until AchE

turnover

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Inhibitory Neuron Blockers

• Tetanus exotoxin • Blocks release of

inhibitory neurotransmitters

• Muscles can’t relax• Spastic paralysis• Opposing flexor and

extensor muscles contract

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Spider Venom• Black widow: causes Ach

release– Lack of inhibitory

neurotransmitters– Spastic paralysis

• Brazilian Wandering Spider and Viagra?– Spider venom increases

NO release– Viagra blocks enzyme that

degrades NO– Most venomous of all

spiders/ more human deaths