Title: Neurotransmitters, Neurotransmitter receptors and their effects
1Neurotransmitters, Neurotransmitter receptors and
their effects
Were talking signals and what they mean to a
neuron! What happens if we block signals?
No specific chapter reading for this.....stick to
the slides!
2General 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
Ca2
3NTS Action
- NT diffuses across synaptic cleft to bind to
receptor (LGC) on postsynaptic membrane - Can generate an electric signal there (EPSPs or
IPSPs)? - 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?
4Neurotransmitters (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
5Small 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 aas
long)? - Met-enkephalin, vasopressin (ADH), many others
www.brainexplorer.org/neurological_control/Neurolo
gical_Neurotransmitters.shtml
6Acetylcholine
- 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/c
holinergic.html
7Glutamate
- 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
8GABA 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
receptorsuse benzodiazepines during ethanol
detox.
- Glycine- also inhibitory
- Mostly in spinal cord and brainstem motor neurons
http//pharma1.med.osaka-u.ac.jp/textbook/Anticonv
ulsants/GABA-syp.jpg
9Catecholamines
Phenylalanine hydroxylase
phenylalanine
- 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 MAOIs!
10DISORDER OF PHENYLALANINE METABOLISMPhenylketonur
ia (PKU)?
- A genetic, autosomal recessive disorder (120,000
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
aas 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/conditionphenylketonuria
11Dopamine
- Parkinsons 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
12Serotonin
- 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
13(No Transcript)
14Ionotropic Receptors
- Nicotinic AChR
- Serotonin Glutamate
- GABAA
- Glycine
15Metabotropic Receptors
- Muscarinic Acetylcholine receptor
- Amanita muscaria
- Parasympathetic effectors stimulated
- Increased saliva, tears, diarrhea
- Antidote is atropine.
- alpha and Beta-Adrenergic receptor
- alpha1-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
16MajorIntracellularTransductionPathwaysUsed by
metabotropic receptors
Signaling molecule
Cell surface receptor
G protein
Effector protein
Late effectors
Target protein
cAMP Pathway
IP3 Pathway
17Signaling by GPCRs
18 - Adenylate cyclase and guanylate cyclase
- Make cyclic AMP and cyclic GMP
19Protein kinase A dissociates when activated by
cAMP
Regulatory subunit
Catalytic subunit
- - Add/remove phosphates to/from enzymes to
activate or deactivate them
20Phosphatases remove phosphorylation kinases add
Better to think in terms of changes in activity
rather than activation (i.e. always basal state
of activation)?
21- adrenergic
- receptor mechanism
PKA
22Inositol Trisphosphate DAG
23Aspects of IP3 signaling
24NT 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
25Drugs and Toxins
- Spastic paralysis vs. flaccid paralysis
26Sodium VGC Blockers
- Lidocaine- used as anesthesia
- Tetrodotoxin-puffer fish and newts (TTX)?
- Saxitoxin- caused by red tide dinoflagellate
accumulates in shellfish (SXT)? - Flaccid paralysis
27Vesicle 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
28mACH-R blocker/ competitor
- Atropine
- Flaccid paralysis
- Smooth muscle, heart, and glands
29nACH-R blocker/ competitor
- Curare
- From tree sap
- Causes flaccid paralysis
- Large dose asphyxiation
30AchE Blockers
- Neostigmine
- Physostigmine
- Spastic paralysis
- Myasthenia Gravis-ptosis
31AchE irreversible inhibitor
- DFP- di-isopropyl fluorophosphates
- Sarin
- Spastic paralysis
- Ventilator until AchE turnover
32Inhibitory Neuron Blockers
- Tetanus exotoxin
- Blocks release of inhibitory neurotransmitters
- Muscles cant relax
- Spastic paralysis
- Opposing flexor and extensor muscles contract
33Spider 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