6/15- Neurochem and Pharm of Brain Disorders Flashcards
Mechanism of transmitter release?
- Voltage-gated Ca ion channels are abundant in nerve terminals
- AP depolarizes nerve terminals and opens Ca channels
- Influx of Ca results in vesicles containing NT to fuse with synaptic membrane and release their contents by exocytosis
- There is interaction between SNARE proteins that promotes exocytosis (in a Ca-dependent process)
- More Ca = more exocytosis
What is SNARE protein?
SNap REceptor
(SNAP = soluble NSF Attachment Protein; NSF = N-ethylamide Sensative Fusion Protein) that mediates/promotes exocytosis
What is the mechanism of Butlnum toxin (BoNT) and Tetanus Toxin (TeNT)?
Capable of cleaving at different places on different SNARE proteins/synaptic proteins
Process of recycling the synaptic vesicle membrane?
- During exocytosis, SNARE proteins stay bound to cell membrane
The fused vesicle is recycled:
- Vesicle gets coated with clathrin
- Dynamin helps release it to cytoplasm
- Clathrin is removed
- Few more steps, the vesicle is ready to get loaded with NT, pick up SNARE proteins, and ready to dock and deliver its cargo
What steps are involved in the synthesis and transport and release of NTs (small molecule and peptide)?
Small molecule transmitters:
- Synthetic enzymes are transported from cell body
Peptide transmitters:
- Precursors and cleavage enzymes are transported from cell body
What disorders are associated with the neuromuscular junction (involving what NT)?
Acetylcholine
- Myasthenia gravis
- Lambert-Eaton syndrome
What is myasthenia gravis?
Treatment?
Autoimmune disorder where Abs against acetylcholine Rs are produced.
Treatment: Neostigmine (inhibitor of AChE)
What is Lambert-Eaton syndrome?
Treatment?
Autoimmune disorder where Abs against pre-synaptic Ca channels are produced
Treatment: no good; plasma exchange, inhibit Ab production, increase pre-synaptic Ca release
What major disease is associated with acetylcholine in the CNS?
Levels high or low?
Symptoms?
Alzheimer’s (memory processes)
- There is a severe loss of cholinergic neurons with people who have Alzheimer’s
- Personality change, dementia, loss of memory
What nuclei in the CNS ar associated with ACh?
Functions?
Nucleus of Meynert
- Involved in learning and memory (consolidation and recall of memory)
Pontine nucleus
- Involved in regulation of forebrain activities
What is the nicotinic ACh receptor (structure, location…)
- 5 subunits, each with 4 trans-membrane domains (TM1-TM4)
- 2 ACh molecules bind to open channel
- Subunit cmposition in: fetal neuromuscular junction, adult neuromuscular junction, ganglia, and cerebral cortex ACh Rs are different
What is the structure/mechanism of muscarinic ACh Rs?
Muscarinic ACh receptors are G-protein coupled (M1-M5)
Steps involved in the synthesis and release of glutamate?
- Glutamate made from glutamine
- Removed by pre-synaptic reuptake
- Also taken up by glial cells and inactivated/converted to glutamine
- Glutamate works on ionotropic and also metabotropic receptors; all EPSP, Na and/or Ca enters cells
What diseases are associated with glutamate?
Excitotoxicity (neuronal cell death) implicated in:
- ALS (Amyotrophic Lateral Sclerosis)
- Alzheimer’s disease
- Epilepsy (inappropriate excitation)
What Glutamate receptor is important in memory? Structure?
NMDA
- Glutamate (NMDA) ionotrophic receptors consist of 5 subunits (each with 4 TMs)
- 2 glutamates bind and Na/Ca enters cell (K leaves); EPSP
How many types of ionotrophic glutamate receptors are there? What are they?
Three:
- NMDA
- AMPA
- Kainate
(In addition, many metabotropic GPCRs)
It is thought that perhaps supplements of __ may result in __?
It is thought that perhaps supplements of glutamate may result in increased memory and more intelligence…
- Oral gluatmine (or glutamic acid) is sold, but no improvement in memory seen and is toxic in large doses
- However, genetic experiments with mice where Glutamate/NMDA transmission was increased resulted in “smarter” mice; downside was that mice also feel more pain (mediated by Substance P)
What NT is associated with increased levels of glutamate?
Substance P (resulting in more pain)
Steps in involved in synthesis and release of GABA?
- Unlike glu, GABA is not incorporated into proteins
- GABA is found only in CNS; not in peripheral nerves or tissues
- GAD (glutamic acid decarboxylase) is a GABA neuron marker; requires Vit B6 (Vit B6 deficiency -> likely seizures)
- GABA made from gutamine -> glutamate -> GABA
- Removed by presynaptic reuptake
- Also taken up by glial cells and inactivated/converted to glutamine
GABA works on what receptors?
Ionotropic, also metabotropic
- All IPSP
- Cl and/or K channels open
What are the diseases associated with GABA?
- Epilepsy (loss of inhibition)
- Also implicated in Parkinson’s, Schizophrenia, senile dementia, and Huntington’s chorea
Structure of GABAa receptor?
- Ionotropic Cl channel
- 5 subunits (4 TMs each)
- 2 GABA mcls bind to open Cl channels
- Cl enters the cell; IPSP; hyperpolarization
Structure of GABAb receptor?
- Metabotropic (Coupled to G proteins)
Steps involved in the synthesis of Catecholamines?
Where does each step take place?
- L-tyrosine
(converted by tyrosine hydroxylase to; cytoplasm)
- L-DOPA
(converted by DOPA decarboxylase to; cytoplasm)
- Dopamine
(converted by dopamine beta-hydroxylase to; vesicle)
- NE (converted by phenylethanolamine N-methyltransferase to; cytoplasm*)
- Epinephrine
*NE leaks of from vesicle into cytoplasm;
Epinephrine is synthesized in the cytoplasm and then transported into the vesicle
Steps involved in the synthesis and release of Dopamine?
Synthesis from tyrosine; rate-limiting/marker enzyme is tyrosine hydroxylase
Removal:
- Reuptake by:
—Pre-synaptic transporter 1 (90%)
—Post-synaptic transporter 2 (minor, ~10%)
- Metabolism by:
—MAO
—COMT
Metabolism by liver is for NTs in periphery; cells in CNS metabolize NTs and release into CSF
Dopaminergic neurons are associated with what main diseases?
- Parkinson’s
- Schizophrenia
How is dopamine distributed in different pathways?
Disease associations?
- Nigro-striatal path (~90%) of CNS dopamine is in this pathway; Parkinson’s
- Meso-limbic path: reward; Drug abuse/ addiction, psychosis
- Meso-cortical system: Psychosis, bipolar disorder
- Hypothalamic-pituitary axis: dopamine inhibits prolactin release
Synthesis and release of NE and E?
- Synthesis and release same as in periphery
- Rs: a1, a2, B1, B2, and B3 (like periphery)
Epinephrine
- Epinephrine release from adrenal medulla and circulates in the blood (periphery) and by nerve terminals (CNS)
- E is widely-distributed in the CNS; function unclear
Norepinephrine
- Low level sin the CNS -> depression
What are several pharmacological methods to treat depression?
- SSRIs: selective serotonin reuptake inhibitors (better than TCAs)
- SNRIs: serotonin, NE reuptake inhibitors to treat depression (do not have the side effects that TCAs have)
- NDRIs: NE Dopamine reuptake inhibitors
Remember: TCAs are addictive, dangerous in overdose, and have many other side effects
Steps involved in the synthesis and release of serotonin?
- How much is in CNS vs. periphery?
- Made from what?
- Inactivated how?
- Mechanism of receptors?
- 90% of body’s serotonin is in periphery (only ~10% in CNS)
- Made from tryptophan
- Inactivated by reuptake
- Most serotonin Rs are GPCRs; exception = 5HT-3 ionotropic channels in vomiting center
Where are the major serotonin-containing neurons and their projections in the CNS?
Associated with what diseases?
- In CNS cortex; low serotonin = depression (SSRIs, SNRIs are antidepressants)
- In vomiting cneter (5-HT3); promotes vomiting (Blockers Ondonsetron/Zofran are important anti-emetics)
- Spinal cord; inhibits the transmission of pain signals
What are the steps involved in the synthesis of nitric oxide?
- Works where?
- Functions in CNS and periphery?
- Diffuses and works on post-synaptic, pre-synaptic neurons and also on glial cells
Functions (periphery): vasodilation
Functions (CNS): not clear; implicated in:
- Regulating synaptic plasticity
- Regulating sleep/wake cycle
- Hormone secretion
- Protect neurons (at physiological concentrations)
- Neurotoxic (kills neurons) at higher concentrations
What are the two broad types of receptors and their underlying mechanisms?
Ionotropic: NT directly binds ion channel
Metabotropic: involves 2nd messengers like cAMP
(channels open due to phosphorylation or physical binding of beta, gabba subunits)
What is the end result of GPCR?
Signaling cascade (depends on signal and target itself)
GPCR in cardiac myocytes?
- Epinephrine (Gs)
- Gs -> AC -> cAMP -> PKA -> Ca channels more likely to open
- -> increased contractility
EPSP in cardiac muscle = contraction
GPCR in smooth muscle?
Epinephrine (Gs)
- Gs -> AC -> cAMP -> PKA -> myosin light chain phosphatsase (MLCP) more active
- Myosin light chain is dephosphorylated
- Result: smooth muscle relaxes
EPSP in smooth muscle = relaxation (opposite cardiac muscle)
Epinephrine (Gq)
- Gq -> IP3 -> Ca -> contraction
GPCR in axon terminal?
Gq -> IP3 -> Ca -> exocytosis
GPCR in neuronal dendrites?
- ACh -> Gq -> IP3 -> Ca
- Ca promotes opening of Cl and K channels
- Hyperpolarization
Name the ionotropic and metabotropic (GPCR) receptors for:
- ACh
- Glutamate
- GABA
- Glycine
- Dopamine
- NE
- E
- Serotonin
- Histamine
- Adenosine
- Opiates
- Substance P
- CGRP
Question:
The neurologic examination of a 60-year old man revealed that he is suffering from Parkinson’s disease. Which one of these following statements is true concerning this disease?
A. It involves degeneration of cholinergic neurons in the basal nucleus of Meynert
B. It involves a degeneration of noradrenergic neurons in the locus ceruleus
C. It involves degeneration of dopaminergic neurons of the substantia nigra
D. Oral administration of dopamine is likely to relieve the symptoms of Parkinson’s disease
E. It is usually associated with hyperkinetic syndrome
Question:
The neurologic examination of a 60-year old man revealed that he is suffering from Parkinson’s disease. Which one of these following statements is true concerning this disease?
A. It involves degeneration of cholinergic neurons in the basal nucleus of Meynert
B. It involves a degeneration of noradrenergic neurons in the locus ceruleus
C. It involves degeneration of dopaminergic neurons of the substantia nigra
D. Oral administration of dopamine is likely to relieve the symptoms of Parkinson’s disease
E. It is usually associated with hyperkinetic syndrome
Question:
Which of the following statements is true regarding NE?
A. The main mechanism for its removal from synaptic cleft involves its reuptake
B. Tyrosine is the immediate precursor for its synthesis
C. Neurons containing NE are present only in the peripheral nervous system
D. Deficiency of this NT in substantia nigra causes Parkinson’s disease
E. It is synthesized in the cytoplasm of the neuronal terminal
Question:
Which of the following statements is true regarding NE?
A. The main mechanism for its removal from synaptic cleft involves its reuptake
B. Tyrosine is the immediate precursor for its synthesis
C. Neurons containing NE are present only in the peripheral nervous system
D. Deficiency of this NT in substantia nigra causes Parkinson’s disease
E. It is synthesized in the cytoplasm of the neuronal terminal
Which one of the statements is true regarding nitric oxide?
A. It’s precursor is alanine
B. It stimulates soluble guanylyl cyclase
C. Tyrosine hydroxylase is involved in its synthesis
D. It mediates its action through NMDA receptors
E. Its actions are mediated by cAMP
Which one of the statements is true regarding nitric oxide?
A. It’s precursor is alanine
B. It stimulates soluble guanylyl cyclase
C. Tyrosine hydroxylase is involved in its synthesis
D. It mediates its action through NMDA receptors
E. Its actions are mediated by cAMP
A neuropathologist received a brain specimen from a deceased Alzheimer’s patient for postmortem histological examination. Which of the following neurological groups is likely to be degenerated in this specimen?
A. Basal nucleus of Meynert
B. Raphe magnus
C. Locus ceruleus
D. Nucleus ambiguus
E. Substantia nigra
A neuropathologist received a brain specimen from a deceased Alzheimer’s patient for postmortem histological examination. Which of the following neurological groups is likely to be degenerated in this specimen?
A. Basal nucleus of Meynert (ACh, Alzheimer’s)
B. Raphe magnus (Serotonin, descending pain control; low serotonin in cortex = depression)
C. Locus ceruleus (azure blue/NE)
D. Nucleus ambiguus (vagus, cardiovascular)
E. Substantia nigra (DA, Parkinson’s)
A 35-year-old woman suffering from migraine headache was prescribed sumatriptan (Imitrex) by her neurologist. The patient’s headache was relieved after she took the drug. Which one of the following mechanisms is responsible for the beneficial effects of sumatriptan in treating migraine headache?
A. It dilates meningeal arteries via beta-2 adrenergic receptors
B. It constricts meningeal arteries via alpha-2 receptors
C. It constricts meningeal arteries via 5-HT1d receptors
D. It dilates systemic arterioles via cholinergic muscarinic receptors
E. It dilates meningeal arteries via histamine Rs
A 35-year-old woman suffering from migraine headache was prescribed sumatriptan (Imitrex) by her neurologist. The patient’s headache was relieved after she took the drug. Which one of the following mechanisms is responsible for the beneficial effects of sumatriptan in treating migraine headache?
A. It dilates meningeal arteries via beta-2 adrenergic receptors
B. It constricts meningeal arteries via alpha-2 receptors
C. It constricts meningeal arteries via 5-HT1d receptors
D. It dilates systemic arterioles via cholinergic muscarinic receptors
E. It dilates meningeal arteries via histamine Rs
When there is Vitamin B6 deficiency, synthesis of which one of the following NTs will be decreased?
A. Glutamate
B. Nitric oxide
C. Serotonin
D. GABA
E. Dopamine
F. Histamine
When there is Vitamin B6 deficiency, synthesis of which one of the following NTs will be decreased?
A. Glutamate
B. Nitric oxide
C. Serotonin
D. GABA
E. Dopamine
F. Histamine
- GAD (Glutamic Acid Decarboxylase) requires Vitamin B6 as coenzyme, thus dietary deficiency of vitamin B6 can lead to diminished GABA synthesis
- In the instance where Vitamin B6 was left out of infant feeding formula, the GABA content in the brain was reduced, resulting in a loss of synaptic inhibition that resulted in seizures and death
