Neurotransmitter Systems (Karius) Flashcards
What controls the ionic gradient?
Membrane permeability to certain ions (ions and large proteins do not freely cross)
Na/K+ ATPase (3 Na out/2 K in, results in chemical gradient with high Na outside cell and high K inside cell)
Action potentials
Exciting “excitable” tissue
What happens to membrane potential during an action potential?
Increases, decreases then returns to RMP
depolarization, repolarization, hyperpolarization
Describe the events of synaptic transmission:
AP arrives at presynaptic terminal > Ca+ channels open causing vesicles with NT release > NT binds to postsynaptic receptor
Ionotropic vs Metabotropic/Serpentine NT receptors:
Ligand gated vs. Second messenger
Metabotropic receptors: Second messengers Gs Gi Gq
- stimulation of adenylate cyclase
- inhibition of adenylate cyclase
- productoin of DAG and IP3 (aka release of intracellular Ca2+)
EPSP (Excitatory Post-synaptic potential)
Binding to receptor opens a cationic channel (either Na+ or Ca2+ > influx of the cation > depolarization
Reach closer to a threshold to generate AP
IPSP (Inhibitory Post-synaptic potential)
Binding to receptor opens an anionic channel (Cl-) > influx of chloride > hyperpolarization
Go further from threshold means less likely to generate AP
Origin of the neurotransmitter:
Area of the brain that makes the NT is where the cell bodies are. Axons may travel really far from the cell body to get to the target
Example: Seratonergic neurons are found in the raphe nuclei = the cell bodies that make the serotonin are found in the raphei nuclei
Post synaptic receptors for serotonin (synapse 1) may be found really far away from this location
What is a tract?
Bundle of axons traveling to the same location
What are the monoamines?
Epinephrine Norepinephrine Dopamine Serotonin Histamine
(created from modifying single amino acids)
END Seton Hall (for rejecting me haha)
Where do you find norepinephrine?
Function?
Locus ceruleus
Other pontine/medullary areas
Wakefulness/alertness
Where do you find epinephrine?
Medulla
Synthesis of epinephrine and norepinephrine:
Tyrosine > ( via tyrosine hydroxylase = rate limiting step) > dopamine > vesicles > norepinephrine > released into synaptic terminal > (via PNMT/phenolethanolamine-N-methyltransferase) > epinephrine > epi moved back into vesicles
How are epinephrine and norepinephrine transported into vesicles?
Inhibitor?
VMAT and VMAT2
Reserpine (leads to synaptic failure)
How are the actions of Epi and Norepi limited?
Reuptake
Enzyme degradation
Which enzymes degrade epi and norepi?
Monoamine oxidase/MAO (metabolites released into ECF)
Catechol-O-methyltransferase/COMT (at glial cells/postsynaptic membrane)
What type of receptors do epi and norepi bind to?
What type of receptors are these?
A-adrenergic
B-adrenergic
-both are serpentine/second messenger type receptors
Where can you find dopamine?
Basal ganglia (motor control) Hypothalamus & limbic system (endocrine and emotional control) Cortex
Synthesis of dopamine:
Tyrosine > ( via tyrosine hydroxylase = rate limiting step) > dopamine
(then to norepi and epi)
How is dopamine action limited?
Reuptake
Catabolism by MAO and COMT (same as norepi and epi)
What receptors does dopamine bind to?
D1 and D5: increase cAMP
D2: decrease cAMP > increases gK causing potassium efflux
D3 and D4: decrease cAMP (aka like D2)
All metabotropic/serpentine receptors that are connected to G proteins
Where is serotonin (5HT) found?
Raphe nuclei in the brainstem (modifies motor activity)
Cerebellum (modifies motor activity)
Hypothalamus and limbic system (mood)
Synthesis of serotonin:
Tryptophan > (via Tryptophan hydroxylase) > Serotonin
How do you limit the action of serotonin?
Reuptake
Catabolism of MAO and COMT
Receptors for Serotonin:
Serpentine receptors:
Ionotropic receptor:
- 5HT1,2,4,5 and 6
- 5HT3
*Roles of these receptors: 5HT2c 5HT3 5HT6 5HT7
- knock out mice are obese and seizure prone
- area postrema (vomiting)
- anti-depressant effect
- limbic system
Where is Histamine located?
Tuberomammillary nucleus of the hypothalamus (wakefulness)
Synthesis of Histamine:
Histidine > (via histidine decarboxylase) > Histamine
How do you limit the action of histamine?
Reuptake
Catabolism by diamine oxidase and COMT
*What are the receptors for Histamine?
What type of receptors?
H1: PLC (phospholipase c) activation
H2: increase cAMP (associated with gastric acid release)
H3: presynaptic, decrease histamine release
All serpentine receptors
Acetylcholine found in?
Striatum of the basal ganglia
Midbrain and pons
Major functions of acetylcholine:
Voluntary motion control (via striatum)
Baseline excitation to cortex (brain arousal/wakefulness)
REM sleep
Synthesis of acetylcholine:
Choline + acetate > vAChT (vesicular Ach transporter protein) moves it into vesicles > Acetylcholinesterase removes it from synaptic trough
*Ach receptors:
Muscarinic
M1 (neuronal) - increase IP3/DAG (Gq)> intracellular Ca+ release
M2 (cardiac) - decrease cAMP via Gi > K+ efflux
M3 (endothelium of vasculature) - increase IP3/DAG (Gq) > intracellular Ca+ release
M4 (presynaptic autoreceptor, striatum of basal ganglia) - decrease cAMP (Gi)
M5 (cerebrovasculature, dopaminergenic neurons of basal ganglia) - increase IP3/DAG
Ach receptors:
Nicotinic
Located at the NMJ (somatic) and synapse 1 (autonomic)
What are the inhibitory neurotransmitters?
GABA
Glycine
GABA:
Major inhibitory amino acid NT
Widely distributed throughout higher levels of the CNS
Spinal cord has least amount of GABA
Roles of GABA:
Consciousness
Motor control
Vision
Synthesis of GABA:
Glutamate > (via glutamate decarboxylase/GAD) > transport into vesicles via VGAT/vesicular GABA transporter protein
Reuptake of GABA:
GAT (GABA transporter) removes it from synapse
GAT 1 is at the presynaptic terminal while GAT 2 is on glial cells surrounding the synapse
If GABA is taken up by GAT1…
If GABA is taken up by GAT2…
-
Repackaged into vesicles as is
-GABA is converted to glutamine > released to the ECF > taken up at presynaptic terminal and recycled to GABA
GABA-A receptors:
Ionotropic (Cl conductance)
Activation produces IPSP in adult neurons
Binding sites also receive Benzo, ethanol and steroids and cause an action potential
GABA-A receptors (outside of synapse terminals)
Large number of such receptors
Site of action for anesthetics like propofol
GABA-B receptors:
Metabotropic
Gi/Go coupled
- activate the GIRK (K+ channel) and inhibit a Ca channel
- Presynaptic receptors regulate NT release while postsynaptic receptors inhibit the post-synaptic cell
Glycine found in?
Function?
Synthesis?
-Spinal cord (mostly), brainstem (particularly in the medulla)
Not much in higher CNS
-spinal inhibitions
-Amino acid is unmodified
Removal of Glycine from synapse:
GAT proteins (same as GAB) Recycling
Glycine receptors:
Ionotropic (responds to chloride) > influx of Cl- leads to IPSP
What other substances bind to glycine receptors?
Ethanol and general anesthetics. Both cause action potential
Stychnine blocks it
What are the purines?
ATP, ADP and Adenosine
ATP and purines:
Synaptic vesicles for Purines all contain ATP. Debate on whether ATP is required for metabolic function
Synthesis of Purines:
ATP by MT > stored in vesicles by VNUT > released > (ATP > ADP > Adenosine) conversion occurs in synaptic trough
Purines are found…
Virtually everywhere in CNS particularly cortex, cerebellum, hippocampus, basal ganglia
Purine receptors :
P1 (A receptors)
Binds adenosine
Role in sleep induction, inhibition of neural function (post synaptic locations)
Role in NT release (presynaptic locations)
Purine receptors:
P2X receptors
Ionotropic
Binds ATP
Purine receptors:
P2Y receptors
Metabotropic
Binds ATP, ADP, UTP and UDP
Gi/Gq coupled
Functions of P2 purine receptors
Learning and memory (co-release with EAA)
Modification of locomotor pathways
Opioid transmitters are what type of transmitters?
Peptide transmitters
Opioids include…
Endorphins
Ekephalins
Dynorphins
Nociceptin
Opioids are found ….
Basal ganglia
Hypothalamus
Multiple pontine and Medullary sites
General functions of opioids:
Modification of nociceptive inputs (cutaneous)
Mood/affect (neurophysiology of emotion/drug addiction)
Precursors for proopiomelanocortinin (POMC, precursor to ACTH):
B-endorphins
Precursors for proenkephalin:
Tyr-gly-gly-phe-X
Met-enkephalin
Leu-enkephalin
Precursors for pro-dynorphin:
3 molecules of Leu-enkephalin
dynorphin
Precursors for Orphanin FQ
nociceptin
Synthesis of Opioids:
Removal in cleft:
- Standard protein synthesis
- reuptake and destruction by enkephalinase and aminopeptidase
Opioid receptors general concepts:
Are all serpentine and activate second messenger systems (Gi/Gq) after ligand binding
Opioid receptors:
U-receptors (Mu)
Metabotropic
Activation causes: analgesia, respiratory depression, euphoria, constipation, sedation
-leads to K+ efflux and hyperpolarization
Opioid receptors:
Kappa (K) receptors
Serpentine
Activation causes: Analgesia, dysphoria, diuresis, miosis
-decrease Calcium influx
Opioid receptors:
Delta receptor
Serpentine receptor
Activation causes: Analgesia
-decrease calcium influx
Endocannabinoids are found …
Basal ganglia (affects mood and motor performance) Spinal cord (modulates nociception) Cortex (neuroprotection) Hippocampus (memory formation) Hypothalamus (energy control/hunger)
Synthesis of Endocannabinoids:
Derived from membrane lipids (arachidonic acid)
Occurs in the presynaptic terminal
Difference in synthesis pathways for Anandamide and 2-AG:
Anandamide - derived from NAPE (N-arachidonoyl phosphatidyl ethanol
2-AG: derived from arachidonoyl-containing phosphatidylinositol bisphosphate (PIP2)
2AG
Major source for arachidonic acid
Manipulation of 2AG has effects beyond the endocannabinoid system
Cannabinoid Receptor 1 (CB1)
Activation = psychoactive responses to cannabinoids
472 AA peptide on chromosome 6
Polymorphisms linked to obesity, ADHD, schizo and Parkinson’s depression
Forms heterodimer with other NT receptors like dopamine and orexin
CB1 distribution:
CNS neurons
Uniform distribution in striatum, thalamus, hypothalamus, cerebellum and lower brain stem
Non-uniform distribution in cortex, amygdala and hippocampus (aka found in only certain neuron types)
Where are cannabinoid receptors usually found?
Binds which molecules with great affinity?
-Presynaptic neurons away from the active zone where the vesicles are
Greater density in inhibitory synapses
-AEA and 2AG
Significance of CB1:
Found on presynaptic terminals of EAA and GABA releasing synapses and reduces EAA and GABA release via a Gi coupled protein
-Anandamide and 2-AG are equally effective in doing this
CB2
Found primarily on macrophages (microglia)
Also found in neurons and usually associated with nerve injury. Inducible in response to injury or inflammation
Binds 2-AG better than AEA
Degradation of Endocannabinoids at the synapse
Hydrolysis
Oxidation via cyclooxygenase and lipoxygenase pathway (both AEA and 2-AG)
Hydrolysis of AEA:
Hydrolysis of 2-AG:
Via Fatty Acid Amide Hydrolase (FAAH)
Via Mono-acyl glycerol lipase (MAGL)
What are the excitatory amino acids:
Glutamate and Aspartate
Locations of EAA
Widely distributed throughout the CNS Most important excitatory NT in the brain. Wide functions
EAA receptors:
Ionotropic
NMDA (N-methyl-D-aspartate receptor)
Activated by Glu, Asp and NMDA (exogenous) and allows influx of calcium
Glycine binding site of the NMDA:
Glycine is required as a co-agonist, but cannot open the channel alone (needs EAA to bind with it)
Mg binding site of the NMDA:
Blocks channel at RMP and prevents CA+ influx
Makes the NMDA receptor both ligand and voltage gated
PCP binding site of NMDA:
Blocks channel
Uses as horse tranquilizer
Non NMDA receptors
Also ionotropic but causes Na influx
2 types: AMPA and Kalnate
AMPA receptors:
-Activated by Glutamate, aspartate and AMPA (exogenous)
Allows Na influx when open
-Benzo binds to this receptor and reduces amount of Na that enters
Kainate receptors:
EAA binds, Na influx with some Ca2+
Activation of the NMDA receptors produce ….
Activation of the non-NMDA receptors produce …
- long latency EPSP with long duration
- EPSP with short duration
Explain the binding of EAA receptors at the postsynaptic terminal?
- Co-localized at the postsynaptic terminal.
- EAA binds to both types of receptors >Na flows into non-NMDA while Ca cannot flow into NMDA because of the Magnesium
- Non-NMDA receptor has a short duration EPSP which causes enough depolarization to make Mg leave the NMDA channel
- with Mg gone, Ca can now enter the NMDA channel and produce the longer lasting EPSP
Functions of the Non-NMDA receptors:
Primary sensory afferents
Upper motor neurons
Functions of NMDA receptors:
Short and long-term memory formation
Synaptic plasticity
EAA Metabotropic receptors
Group 1
Group 2 and 3
- Gq coupled (glu 1 and 5)
- Gi coupled (glu 2-8)
Presynaptic Metabotropic receptors
Post synaptic Metabotropic receptors
- NT release control
- learning, memory, motor systems
How is the action of the EAA limited?
EAA released into synapse > Glial cell uptakes and converts EAA to glutamine > glutamine reuptake by presynaptic neuron > converted back to glutamate (EAA) > released again
Nitric oxide and NMDA receptors
NMDA activation can lead to production of NO.
How? NMDA binds and triggers Ca2+ influx > Ca2+ activates calcineurin which activates NOS (Nitric oxide synthase) > cleaves Arg to produce NO
Properties of NO:
Lipid soluble. Diffuses back to presynaptic neuron and affects it
Neural functions of NO:
Long term potentation of memory in hippocampus & cerebellum
Cardiovascular and respiratory control in pons and medulla
Non-neural functions of NO:
Immunological: released by macrophages to poison pathogens
Cardiovascular: vasodilation of smooth muscle
Downside of NO:
Unstable (half life is 5 seconds)
Leads to production of free radicals and toxic to neurons in high concentrations
