6/15- Neurochem and Pharm of Brain Disorders

Question 1

Mechanism of transmitter release?

Answer 1

• 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

Question 2

What is SNARE protein?

Answer 2

SNap REceptor

(SNAP = soluble NSF Attachment Protein; NSF = N-ethylamide Sensative Fusion Protein) that mediates/promotes exocytosis

Question 3

What is the mechanism of Butlnum toxin (BoNT) and Tetanus Toxin (TeNT)?

Answer 3

Capable of cleaving at different places on different SNARE proteins/synaptic proteins

Question 4

Process of recycling the synaptic vesicle membrane?

Answer 4

• 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

Question 5

What steps are involved in the synthesis and transport and release of NTs (small molecule and peptide)?

Answer 5

Small molecule transmitters:

• Synthetic enzymes are transported from cell body

Peptide transmitters:

• Precursors and cleavage enzymes are transported from cell body

Question 6

What disorders are associated with the neuromuscular junction (involving what NT)?

Answer 6

Acetylcholine

• Myasthenia gravis
• Lambert-Eaton syndrome

Question 7

What is myasthenia gravis?

Treatment?

Answer 7

Autoimmune disorder where Abs against acetylcholine Rs are produced.

Treatment: Neostigmine (inhibitor of AChE)

Question 8

What is Lambert-Eaton syndrome?

Treatment?

Answer 8

Autoimmune disorder where Abs against pre-synaptic Ca channels are produced

Treatment: no good; plasma exchange, inhibit Ab production, increase pre-synaptic Ca release

Question 9

What major disease is associated with acetylcholine in the CNS?

Levels high or low?

Symptoms?

Answer 9

Alzheimer’s (memory processes)

• There is a severe loss of cholinergic neurons with people who have Alzheimer’s
• Personality change, dementia, loss of memory

Question 10

What nuclei in the CNS ar associated with ACh?

Functions?

Answer 10

Nucleus of Meynert

• Involved in learning and memory (consolidation and recall of memory)

Pontine nucleus

• Involved in regulation of forebrain activities

Question 11

What is the nicotinic ACh receptor (structure, location…)

Answer 11

• 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

Question 12

What is the structure/mechanism of muscarinic ACh Rs?

Answer 12

Muscarinic ACh receptors are G-protein coupled (M1-M5)

Question 13

Steps involved in the synthesis and release of glutamate?

Answer 13

• 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

Question 14

What diseases are associated with glutamate?

Answer 14

Excitotoxicity (neuronal cell death) implicated in:

• ALS (Amyotrophic Lateral Sclerosis)
• Alzheimer’s disease
• Epilepsy (inappropriate excitation)

Question 15

What Glutamate receptor is important in memory? Structure?

Answer 15

NMDA

• Glutamate (NMDA) ionotrophic receptors consist of 5 subunits (each with 4 TMs)
• 2 glutamates bind and Na/Ca enters cell (K leaves); EPSP

Question 16

How many types of ionotrophic glutamate receptors are there? What are they?

Answer 16

Three:

• NMDA
• AMPA
• Kainate

(In addition, many metabotropic GPCRs)

Question 17

It is thought that perhaps supplements of __ may result in __?

Answer 17

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)

Question 18

What NT is associated with increased levels of glutamate?

Answer 18

Substance P (resulting in more pain)

Question 19

Steps in involved in synthesis and release of GABA?

Answer 19

• 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

Question 20

GABA works on what receptors?

Answer 20

Ionotropic, also metabotropic

• All IPSP
• Cl and/or K channels open

Question 21

What are the diseases associated with GABA?

Answer 21

• Epilepsy (loss of inhibition)
• Also implicated in Parkinson’s, Schizophrenia, senile dementia, and Huntington’s chorea

Question 22

Structure of GABAa receptor?

Answer 22

- Ionotropic Cl channel

• 5 subunits (4 TMs each)
• 2 GABA mcls bind to open Cl channels
• Cl enters the cell; IPSP; hyperpolarization

Question 23

Structure of GABAb receptor?

Answer 23

• Metabotropic (Coupled to G proteins)

Question 24

Steps involved in the synthesis of Catecholamines?

Where does each step take place?

Answer 24

• 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

Question 25

Steps involved in the synthesis and release of **Dopamine**?

Answer 25

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

Question 26

Dopaminergic neurons are associated with what main diseases?

Answer 26

- Parkinson's - Schizophrenia

Question 27

How is dopamine distributed in different pathways? Disease associations?

Answer 27

1. **Nigro-striatal path** (~90%) of CNS dopamine is in this pathway; Parkinson's 2. **Meso-limbic path**: reward; Drug abuse/ addiction, psychosis 3. **Meso-cortical system**: Psychosis, bipolar disorder 4. **Hypothalamic-pituitary axis**: dopamine inhibits prolactin release

Question 28

Synthesis and release of NE and E?

Answer 28

- 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

Question 29

What are several pharmacological methods to treat depression?

Answer 29

- **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

Question 30

Steps involved in the synthesis and release of **serotonin**? - How much is in CNS vs. periphery? - Made from what? - Inactivated how? - Mechanism of receptors?

Answer 30

- **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

Question 31

Where are the major serotonin-containing neurons and their projections in the CNS? Associated with what diseases?

Answer 31

- 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

Question 32

What are the steps involved in the synthesis of nitric oxide? - Works where? - Functions in CNS and periphery?

Answer 32

- 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

Question 33

What are the two broad types of receptors and their underlying mechanisms?

Answer 33

**Ionotropic**: NT directly binds ion channel **Metabotropic**: involves 2nd messengers like cAMP (channels open due to phosphorylation or physical binding of beta, gabba subunits)

Question 34

What is the end result of GPCR?

Answer 34

Signaling cascade (depends on signal and target itself)

Question 35

GPCR in **cardiac myocytes**?

Answer 35

**- Epinephrine (Gs)** - Gs -\> AC -\> cAMP -\> PKA -\> Ca channels more likely to open - -\> increased contractility **EPSP in cardiac muscle = contraction**

Question 36

GPCR in **smooth muscle**?

Answer 36

**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

Question 37

GPCR in **axon terminal**?

Answer 37

Gq -\> IP3 -\> Ca -\> exocytosis

Question 38

GPCR in **neuronal dendrites**?

Answer 38

- ACh -\> Gq -\> IP3 -\> Ca - Ca promotes opening of Cl and K channels - Hyperpolarization

Question 39

Name the ionotropic and metabotropic (GPCR) receptors for: - ACh - Glutamate - GABA - Glycine - Dopamine - NE - E - Serotonin - Histamine - Adenosine - Opiates - Substance P - CGRP

Answer 39

Question 40

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

Answer 40

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 41

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

Answer 41

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 42

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

Answer 42

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

Question 43

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

Answer 43

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)

Question 44

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

Answer 44

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

Question 45

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

Answer 45

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