Module 2D (Pt3)

Question 1

What are the junctional transmission steps

Answer 1

1. Storage and release of the transmitter
   
   2. Post junctional potential
   3. Initiation of post junctional activity
   4. Destruction or dissipation of the transmitter
   5. Non electrogenic functions

Question 2

Storage and release of the transmitter

Answer 2

the neurotransmitter is packed into synaptic vesicles in the axon

Question 3

Post junctional potential

Answer 3

the transmitter crosses the synaptic cleft, interacts with a receptor and evokes a response from the post synaptic neuron

Question 4

Initiation of post junctional activity

Answer 4

summation of responses caused by the transmitter(s) results in a change in the post synaptic neuron

Question 5

Destruction or dissipation of the transmitter

Answer 5

enzymes, reuptake pumps, or simple diffusion limit the transmitters signal

Question 6

Non electrogenic functions

Answer 6

continual quantal release is a homeostatic control for maintaining receptor, enzyme and pump levels

Question 7

What are receptors

Answer 7

• Biological molecules (often proteins) that are selective in their ligand-binding characteristics and modifiable when a ligand is bound so as to produce a functional change

Question 8

What is a receptor site for a drug (ligand)

Answer 8

• Is the specific binding region of the receptor
  
  • Has a high and selective affinity for the drug molecule

Question 9

What initiates the action of the drug

Answer 9

• The interaction of a drug and its receptor

Question 10

Receptor

Answer 10

a molecule to which a drug binds to bring about a change in a biological system

Question 11

Receptor site

Answer 11

specific region of the receptor molecule to which a drug binds to

Question 12

Effector

Answer 12

component of the system that accomplishes the biological effect

Question 13

Spare receptor

Answer 13

receptor that doesn’t bind agonist when drug concentration is sufficient to produce max effect Kd> EC50

Question 14

Agonist:

Answer 14

a drug that activates its receptor

Question 15

Antagonist

Answer 15

a drug that binds without activating its receptor and prevents activation by agonist
-(competitive, irreversible, physiologic, chemical, inverse)

Question 16

What causes regulation in receptors

Answer 16

• Number, location, interaction with effectors
  
  • Desensitization, tachyphylaxis (become down regulated if over used)
  • Internalization
  • Substrate depletion
  • Down or up regulation

Question 17

What are ionotropic receptors

Answer 17

• Ligand-gated ion channels
  
  • Rapid response (microseconds)
  • Often more then 1 subunit (oligomeric
  • Examples are nAChR (Ach receptor, Na channel)

Question 18

What are metabotropic receptors

Answer 18

• G protein coupled receptors
  
  • Slower, modulatory response (milliseconds/ seconds)
  • Single 7 helix subunit
  • Example is mAChR (Ach receptor)
  • BAR (norepinephrine receptor)

Question 19

Cholinergic transmission steps

Answer 19

i) Acetylcholine synthesis
ii)Choline transport and storage
iii)Release of Ach by SNAREs: CAMPs and SNAPs
iv)Ach degradation

Question 20

Acetylcholine synthesis

Answer 20

• Occurs through choline acetyltransferase (ChAT)
  i) ChAT transfers an acetyl group from acetyl-CoA onto choline
  ii) Acetyl- CoA synthesized by pyruvate dehydrogenase in mitochondria
  iii) Choline is brought into the axon terminal by active transport

Question 21

Choline transport and storage

Answer 21

• Occurs through the enzymes choline transporter (CHT1) and vesicular Ach transporter (VAChT)
  i) CHT1 brings choline into the axon
  
  • ATP- dependent (active transport), rate limiting
  • Inhibited by hemicholiunium (not used clinically rather for research)
    ii) CAChT brings Ach into synaptic vesicles
  • Atp dependent
  • Inhibited by vesamicol
  • 1,000- 50,000 Ach/ vesicle
  • About 300,000 vesicles in an axon

Question 22

Release of Ach by SNAREs: VAMPs and SNAPs

Answer 22

i) When an axon terminal depolarizes
- Voltage gates Ca channels open
- Ca allows for interactinos between Vesicle-associated Membrane proteins (VAMPs) and synaptosome associated proteins (SNAPs) on the vesicles and membrane
- Membrane fusion occurs, allowing Ach (and co trasnmitters) to exit the cell by exocytosis
- Ach release is inhibited by botulinum toxin
ii) 2 ACh pools
- The readily releasable pool
- The reserve pool

Question 23

Ach degradation

Answer 23

• Occurs through acetylcholinesterase (AChE)
  i) Ach Is broken down quickly in the synaptic cleft
  
  • AChE hydrolyzes Ach into acetate and choline, both are recycled
  • Ach is present in the synapse or neuromuscular junction for < 1 millisecond
  • Inhibition of AChE is therapeutically important (and potentially toxic) effect of many drugs

Question 24

If you were to give someone botulism toxin would you be promoting or inhibiting the sympathetic nervous system

Answer 24

• Net effect is blocking ach so your promoting sympathetic nervous system as you are inhibiting the parasympathetic
  - Look at the end effector

Question 25

How many homologous subunits are in nicotinic acetylcholine receptor

Answer 25

- 5 homologous subunit form Na+/K+ pore - Subdivided based on location and their ability to bind a bungarotoxin

Question 26

What are m nAChR

Answer 26

Muscle receptor

Question 27

Where are Neuronal type nAChR:

Answer 27

- Exist in peripheral ganglia, adrenal medulla, and brain as homopentamers and heteropentamers (Nn)

Question 28

What do peripheral Nn

Answer 28

Depolarization and firing of post ganglionic neurons, secretion of catecholamines

Question 29

What are muscarinic acetylcholine receptors

Answer 29

- Get name from muscimol, from mushrooms (mimics and activates the effects of the parasympathetic nervous system) - 5 distinct subtype (1-5) - All GPCRs with different roles

Question 30

What are the Gq coupled GPCRs

Answer 30

- M1,3,5 Important in smooth muscle fibers (in gut, eye…)

Question 31

What are the Gi coupled GPCRs

Answer 31

- M2,4 - I stands for inhibitory - Does three things all at the same time - Found mainly on muscles of heart (heart slows down)

Question 32

Cholinergic actions in the body (Skeletal muscle, Autonomic ganglia, autonomic effector cells, Prejunctional sites, extra neuronal sites)

Answer 32

1. Skeletal muscle - Ach released from motor nerve-> nAChR open-> skeletal muscle-> contraction 2. Autonomic ganglia - Ach released from pre-ganglionic nerve-> nAChR open -> EPSP in post ganglionic nerve 3. Autonomic effector cells - Ach released from post-ganglionic PNS nerve -> mAChR activated -> electrical activity is modulated - Heart SA and AV nodes: increase K, hyperpolarization --> slowed heart rate - Smooth muscle: Increase Na, Ca --> partial depolarization contraction via Ca 4. Prejunctional sites - Negative feedback via M2 and M4 5. Extra neuronal sites

Question 33

What are cholinomimetics also called

Answer 33

- Parasympathomimetic

Question 34

What are cholinomimetics clinically useful

Answer 34

- Glaucoma - Loss of normal function in bowel and bladder - Smoking cessation

Question 35

Muscarinic toxicity

Answer 35

- Miosis, bronchoconstriction, excessive GI activity, sweating, vasodilation, slowing of heart rate followed by reflex tachycardia (vagus nerve kicks in)

Question 36

Explain nicotinic toxicity

Answer 36

- Fasciculations and paralysis, stimulation (convulsions) and then depression, addiction

Question 37

What happens when AChE is inhibited

Answer 37

- DUMBBELSS - Diarrhea, urination, miosis, bronchoconstriction, bradycardia, excitation (skeletal muscle and CNS), lacrimation, salivation, sweating

Question 38

What are muscarinic antagonists clinically useful in

Answer 38

- Scopolamine: nausea - Atropine: treating miosis, reducing airway secretion, reducing diarrhea and gastric secretions (in the past), treating AChE intoxication - Ipratropium: bronchodilation in asthma - Oxybutynin: bladder spasm

Question 39

Toxicity in muscarinic antagonists

Answer 39

- Hyperthermia (through inhibition of sweating), dry mouth, tachycardia, arrhythmia, acute angle glaucoma, urinary retention, constipation, blurred vision, flushing (redness), sedation, delirium and hallucinations

Question 40

What are nicotinic antagonists useful in (clinically)

Answer 40

- Hypertensions (hexamethonium)

Question 41

Are nicotinic antagonists used clinically often

Answer 41

Rarely used clinically

Question 42

Toxicity of nicotinic antagonists

Answer 42

- Venous pooling and postural hypotension - Dry mouth, blurred vision - Constipation - Sexual dysfunction

Question 43

look at extending concepts