What is neuromodulation?
A substance that modifies the sensitivity of synaptic stimulation or inhibition by acting on a neuron
What are the 4 classes of neuromodulators?
- Esters
- The amines
- Amino acids
- Gases
List the neuromodulators under each class
Class I: Esters
Acetylcholine
Class II: The Amines
- Catecholamines:
Dopamine, norepinephrine, epinephrine,
-Serotonin, Histamine
Class III: Amino Acids Glutamate Aspartate γ-Aminobutyric acid (GABA) Glycine
Class IV: Gases Nitric oxide (NO)
What are the classes of neurotransmitters?
- Amine (main)
- Amino acids
- Neuropeptides
- Purines and pyrimidines
- Gases
- Lipids
List some lipid neurotransmitters
Anandamide, prostaglandins and neurosteroids
List some gases as neurotransmitters
NO and CO
NB: NO are in postsynaptic neurons and modify the length of excitablity
They may play a role in memory
List some neuropeptides
Substance P, Vasopressin, endorphins, neurotensins
Where are neuropeptides synthesized?
By ribosomes in the neuronal cell body
Compare the action, storage of the amines, amino acids and neuropeptides
Amines are rapidly acting and they act on ion channels. They are stored in small dense vesicles.
Amino acids are rapidly acting and act on ion channels as well. They are stored in small clear vesicles.
There is reuptake and recycling of vesicles by both amino acids and amines
Neuropeptides are slow acting and are stored in large dense vesicles. They act through second messenger systems to cause long term changes in metabolism of neuron.
What is the purpose of Ca2+ in neurotransmitter release?
Ca2+ is needed in synaptic vesicle budding, fusion and discharge
What is the purpose of clathrin?
After neurotransmitter release, the vesicular membrane is coated with the protein clathrin - identifying it for recycling.
The clathrin coated pits are transferred to the endosome, where the membrane is reused for new vesicles and refilled with neurotransmitter.
What are ionotropic NT receptors?
- Ligand gated ion channels– NT binding causes ion pore or channel to open
- Fast neurotransmission
- Short-lived response
- Inhibitory NTs cause Cl- influx and hyperpolaristion
- Excitatory NTs cause Na+ influx and depolarisation
E.g.: nAchR, GABAA, glycine and glutamate (AMPA/NMDA/Kainate) receptors
What is the difference between cation and anion ionic channels?
Cation channels are lined with negative charges. Allow mainly Na+ ions to pass but sometimes K+ or Ca2+ ions. These channels are excitatory
Anion channels are lined with positive charges. Allow mainly Cl- ions to pass. These are inhibitory transmitters
What are metabotropic NT receptors
•NT binding activates G protein which then activates channels or second messenger systems
• Slow neurotransmission
• Longer duration of action
• E.g.: mAchR, D1/D2,
adrenoreceptors, most 5-HT receptors, mGluR, GABAB
What is the difference between metabotropic and ionotropic NT receptors?
Ionotropic NT receptors have fast neurotransmission and short-lived responses. It opens directly on NT binding. Can be inhibitory or excitatory,
Metabotropic NT receptor has slow neurotransmission and longer duration of action. On binding to metabotropic receptors (G-protein) it will activate other channels or second messenger systems.
Where is serotonin found?
In the raphe nuclei located in the brainstem
What is the name of the glutamate transporter that removes glutamate?
EAAT
List the glutamate receptors for excitatory effect
• Ionotropic
– NMDA
– AMPA
– Kainate /quisqualate
• Metabotropic
– mGluR (1-8)
Function of NMDA receptor
Requires both ligand (neurotransmitter) and depolarization to open.
Blocked by Mg2+
Depolarization displaces Mg2+ ions
Channel become permeable to Na+ and Ca2+ when Mg2+ is displaced
Glycine is the main inhibitory NT in the spinal cord and brainstem but GABA is the main inhiboty NT in the>
Brain, primarly found in interneurons
Glutamate is a major excitatory NT and is synthesized from glutamine by glutaminase.
Which inhibitory NT does glutamate form?
GABA via glutamic acid decarboxylase
GABA and glutamate are stored in small clear vesicles. What are they packaged in?
GABA is packaged into VGAT vesicles.
Glutamate is packaged into vGlut vesicles
How are gaba and glutamate removed?
Reuptake into nerve terminals or glial cells by specific membrane transport systems
- GABA reuptake into nerve terminals for recycling
- Glutamate uptake by glia
What are the two types of GABA receptors?
GABA-A and GABA-B
Differentiate b/w GABA-A and GABA-B
• GABA A – Ionotropic – Chloride channel – Activation causes hyperpolarization – Other agonists: BZDs, barbiturates.
• GABA B – Metabotropic – Leads to increased efflux of K+ and hyperpolarization – Also leads to decreased presynaptic Ca2+ influx – Agonist: baclofen, ?gabapentin
Where is gylcine synthesized from?
Serine
Glycine is taken up by?
GLYT transporters
What is the antagonist to glycine?
Strychnine
Types of glycine receptors
α, β:
– Ionotropic
– Chloride channels
– Hyperpolarization
Where are enkephalins and dynorphins found?
found in the periaqueductal gray and dorsal horn of spinal cord
What are the functions of enkephalins and dynorphins?
inhibit the flow of pain information to the brain.
They are endogenous opiod peptides
Receptors are Mu, kappa and delta
Where are endorphins found?
In the hypothalamus
Which family does substance p belong to?
Tachykinins
Where is substance P found?
Found in:
- Primary afferent nerve endings (C fibres),
- Substantia gelatinosa of cord,
- Substantia nigra
What is the receptor of substance P?
neurokinin-1
What is the role of substance P?
pain transmission / inflammation, nausea,
mood/depression, migraine
Dopamine binds to
dopaminergic receptors of substantia nigra of midbrain and hypothalamus
What is peroxyanitrite?
Combination of NO and superoxide anions (O2-) –> peroxynitrite (ONOO-)
Peroxynitrite is an oxidizing free radical that can cause DNA fragmentation and lipid oxidation
Plays a role in memory through Long Term Potentiation in the hippocampal formation.
In hypoxia Cortical areas are more sensitive to hypoglycaemia than the vegetative centers of the brain stem
In hypoxia Cortical areas are more sensitive to hypoglycaemia than the vegetative centers of the brain stem
Energy needed in the brain for what purpose?
Maintain the ionic gradient across nerve membranes. Ionic transport in the neurons mainly to transport Na+ and Ca2+ to the outside an K+ to the inside
Oxidation of non-glucose substrates
ketones/lactate during prolonged fasting.
High metabolic rate , hypoxia to brain for more than 10 sec causes unconsciousness
High metabolic rate , hypoxia to brain for more than 10 sec causes unconsciousness
How does glucose enter the brain?
via GLUT 1 in cerebral capillaries
Insulin is NOT required for cerebral cells to utilize glucose
Where is glycogen stored?
primarily stored in astrocytes
During prolonged starvation, beta-hydroxybutyrate and acetoacetate replaces glucose as the predominant fuel for brain metabolism
During prolonged starvation, beta-hydroxybutyrate and acetoacetate replaces glucose as the predominant fuel for brain metabolism
What is the purpose of glut 1 and glut3 and 5?
GLUT1 :localized in microvessels of the blood-brain barrier. Moves glucose from the capillary lumen to the brain interstitium.
GLUT3 / GLUT5: transport glucose from interstitium into neurons and glial cells.
P-glycoprotein
Transport various proteins and lipis across membrane via ATP binding
What is the purpose of Na+K+2Cl- co-transporter?
It is stimulated by ET-1 and ET-3 (ET-endothelin).
Helps keep brain K+ concentration low
What is the body’s response to hypoglycemia?
Hypoglycemia is recognised in the ventromedial hypothalamus (glucose sensor)
Epinephrine: Triggered at ~70 mg/dL of blood glucose. Accompanied by many classic symptoms of hypoglycemia – shakiness, trembling, nervousness, and tachycardia.
In type 1 or type 2 diabetes, glucagon secretion becomes defective, epinephrine secretion becomes the critical counterregulatory factor.
What is the multiorgan effect due to hypoglycemia?
Multiorgan effects
(1) drives glycogenolysis,
(2) stimulates gluconeogenesis in the liver and kidney,
(3) decreases peripheral glucose uptake,
(4) stimulation of lipolysis.
What is the function of growth hormone/cortisol on hypoglycemia?
It is a slow acting hormone , acts 3hrs after hypoglyemia
Functions:
(1) systemic glucose production
(2) suppressing peripheral glucose oxidation and use
(3) lipolysis.
What is the function of the liver in hypoglycemia?
(30 to 35 mg/dL), in the absence of counterregulatory hormones. (glycogenolysis and gluconeogenesis ).
At a level of 76 - 72 mg/L of glucose in the blood which hormone is suppressed?
Insulin
At 67mg/dL which hormones are increased?
Counterregulatory hormones of insulin are increased i.e glucagon, epinephrine, and growth hormone/cortisol
What are the effects of ammonia on nerve cells?
Ammonia is very toxic to nerve cells.
Ammonia toxication is believed to be a major cause of the bizarre neurologic symptoms in hepatic coma.
What makes ammonia toxic to the nerve cells?
It reacts with ketoglutarate to form glutamate. The resulting depleted levels of -ketoglutarate then impair function of the tricarboxylic acid (TCA) cycle in neurons.
Rises in cerebral blood flow due to hypoxia, hypercapnia (raised blood CO2) will cause a rise in ICP
CBF is maintained by the process of autoregulation.
The normal cerebral blood flow is 45-50ml100g-1min-1,
when the flow falls to less than 18-20ml100g-1min-1, physiological electrical function of the cell begins to fail.
What are the energy requirements for white vs gray matter?
- White matter: 20-50ml/100g/min
2. Gray matter : as high as 100ml/100glmin
Brain maintains cerebral blood flow through autoregulation. What is autoregulation?
Autoregulation is a change in cerebral perfusion pressure resulting in a compensatory change in vessel caliber.
A drop in CPP produces vasodilatation
A rise in CPP produce vasoconstriction