1.10B. Sympathetic efferent mechanisms, adrenergic receptors.

Question 1

I. What are the characteristics of SYM nervous system?

Answer 1

• SYM nervous transmission has a ‘’thoracolumbar’’ origin in that the preganglionic fibers come from the thoracic and lumbar spinal cord
• These preganglionic fibers are relatively short before synapsing in a ganglion with nicotinic ACh receptors on the postganglionic neuron
• Postganglionic neuron is relatively long and travels to its target effector organ, usually using norepinephrine as the NT (with different α or β adrenergic receptor effects)
  -> In the case of the adrenal gland, the preganglionic neuron goes directly to the adrenal gland medulla, causing it to release both E (80%) and NE (20%)

Question 2

II. Anatomy of sympathetic nervous system
1. Origin?

Answer 2

Thoracic Spinal Cord (T1-T12)
Lumbar (L1-L2/L3)

Question 3

II. Anatomy of sympathetic nervous system
2. Ganglion?

Answer 3

Close to spinal cord (prevertebral and paravertebral ganglia)

Question 4

II. Anatomy of sympathetic nervous system
3. Sizes of Preganglionic and Postganglionic axons

Answer 4

Pre - Short
Post - Long

Question 5

II. Anatomy of sympathetic nervous system
4. Preganglionic Transmitter?

Answer 5

ACh

Question 6

II. Anatomy of sympathetic nervous system
6. Postganglionic Axon Transmitter

Answer 6

NE
(Ach: sweat glands)

NE-NPY in GI vessels
NE- Somatostatin
NE - ATP

Question 7

II. Anatomy of sympathetic nervous system
7. Receptors of the effector cells

Answer 7

Adrenergic receptors

α1 (IP3, Ca2+ ↑)
α2(cAMP↓)
β1 (cAMP↑)
β2 (cAMP↑)
β3 (cAMP↑)

mAChR

Question 8

II. Anatomy of sympathetic nervous system
8. What are the 3 mechanisms of Elimination of Transmitters?

Answer 8

1. NE Reuptake
2. Degradation in cytoplasm
3. Diffusion

Question 9

II. Anatomy of sympathetic nervous system
9. What are the 3 mechanisms of Modulating Transmitter Balance?

Answer 9

• Membrane NE-transporter inhibition (cocaine)
• Inhibiting NE carrier in vesicle membrane
• Blocking NE synthesis

Question 10

III. Adrenergic receptors
1. What are the characteristics of adrenergic receptors?

Answer 10

• Adrenergic receptors can be activated by either NE or E, with the receptor types having differing binding activity
• There are 2 α-type and 3 β-type adrenergic receptors
• An acronym to remember their GPCRS is ‘’QISSS’’, where Gq for α1 and so on
  -> α1, α2, β1, β3, β3 (QISSS)

Question 11

III. Adrenergic receptors
2A. Where can you find α1 receptors (Gq)?

Answer 11

• Found in vascular smooth muscle of skin, skeletal muscle, and splanchnic region
• Also, in the Sphincter of GI tract and bladder

Question 12

III. Adrenergic receptors
2B. What are effects of α1 receptors (Gq) on organs?

Answer 12

Contraction of vessels, sphincters, and radial muscle of iris

Question 13

III. Adrenergic receptors
2C. Characteristics of α1 receptors (Gq)

Answer 13

• Activation leads to contraction!
  -> Binding affinity: NE>E

Question 14

III. Adrenergic receptors
2D. What is the mechanism of of α1 receptors (Gq)

Answer 14

Gq
-> PLC -> formation of IP3 + DAG from PIP2
- IP3 releases SR/ER-stored Ca2+ into cytosol
- DAG + [Ca2+]IC activates PKC -> Phosphorylation of target proteins

Question 15

III. Adrenergic receptors
3A. The role of α2-receptors (Gi)

Answer 15

Inhibition of further NE release (SYM) or ACh release (PARA)

Question 16

III. Adrenergic receptors
3B. How do α2-receptors (Gi) work on sympathetic postganglionic nerve terminals?

Answer 16

1/ will upon activation -> inhibit further release of NE from the same terminal
2/ This is a negative feedback mechanism that conserves NE in states of prolonged SYM stimulation (Adrenal medulla is NOT a subject to this regulation, so it can be depleted of catecholamines during periods of prolonged stress!)

Question 17

III. Adrenergic receptors
3C. How do α2-receptors (Gi) work on parasympathetic postganglionic nerve terminals?

Answer 17

1. will upon activation cause inhibition of release of ACh and this inhibits GI-function
2. The mechanism of action involves the inhibition of adenylyl cyclase and thus decrease of cAMP levels.

Question 18

III. Adrenergic receptors
4A. What are the effects of of β1-receptors (Gs) on organs?

Answer 18

HR ↑, conduction velocity ↑, contractility ↑, and Renin secretion↑

Question 19

III. Adrenergic receptors
4B. What are the locations of of β1-receptors (Gs)?

Answer 19

1. Prominent in the heart – present in the SA, AV nodes, and ventricular muscle.
2. located in salivary glands, adipose tissue, and very importantly the kidney (promotes renin secretion.)

Question 20

III. Adrenergic receptors
4C. What does Activation of β1-receptors (Gs) lead to?

Answer 20

Activation leads to:
o Increased heart rate (chronotropy) in the SA node
o Increased conduction velocity (dromotropy) in the AV node
o Increased contractility (inotropy) of the ventricular muscle

Question 21

III. Adrenergic receptors
4D. What is the mechanism of β1-receptors (Gs)?

Answer 21

Gs protein
-> Adenylyl cyclase -> increasing cAMP levels.

(cAMP is a second messenger for a variety of tissue-dependent stimulatory physiological activities.)

Question 22

III. Adrenergic receptors
5. Characteristics of β2-receptors (Gs)

Answer 22

• β2-receptors (Gs) -> relaxation/dilation of vessels (E&raquo_space; NE)
• Same Gs mechanism but different receptor
• Found in vascular smooth muscle within the Heart and Lungs (bronchioles).
• Leads to relaxation/dilation of SM in both places to provide increased blood flow and oxygenation – when E is released
• β2 receptors (Gs) -> increased cAMP
  -> cAMP inhibits MLCK -> SM Relaxation!

Question 23

III. Adrenergic receptors
6. The role of β3-receptors (Gs)

Answer 23

1/ Lipolysis in adipose tissue
2/ Thermogenesis in skeletal muscle.

Question 24

III. Adrenergic receptors
7. How does sympathetic nervous system use adrenergic receptors in overall?

Answer 24

• SYM stimulation leads to contraction of most vascular SM with α1 receptors (Gq) - BUT SYM stimulation also leads to vasodilation in some important blood vessels via β2
  receptors -> The two opposing effects are competitive based on concentration of E
• The normal state is some level of vasoconstriction with α1 receptors (Gq) dominance. However, in an emergency, E is released and dilates blood vessels in the heart and lungs via β2 receptor, plus cardiac output is increased with β1 receptor

Question 25

III. Adrenergic receptors
8. Make a summary table of Adrenergic receptors

Answer 25

Question 26

IV. Important extra stuff
1. What are characteristics of Sympathetic adrenergic varicosities

Answer 26

1/ A single axonal branch can influence higher number of targets
2/ Sympathetic postganglionic adrenergic nerves release their neurotransmitters from varicosities (like beads, which acts like presynaptic membrane) onto their target tissue.
3/ Content of varicosities include tyrosine, dopamine β-hydroxylase, ATP, neuropepetide Y)

Question 27

IV. Important extra stuff
2. How does Synthesis of epinephrine occur in the adrenal medulla?

Answer 27

• Preganglionic neuron synapses on chromaffin cells of adrenal medulla, and then releases Ach and activates nicotinic receptors. (no postganglionic)
• When activated, chromaffin cells secrete catecholamines (NE and E) into general circulation.
• Adrenal medulla secretes mainly epinephrine (80%) and a bit of norepinephrine as well (20%).
  *epinephrine is only released from adrenal medulla in human yo!
• NE→E is catalyzed by phenylethanolamine-N-methyltransferase (PNMT), which requires cortisol from nearby adrenal cortex.

Question 28

V. Pharmacology
1. Examples of Sympathomimetic drugs (sympathetic stimulation)

Answer 28

Direct
1. adrenergic receptor agonist (epinephrine, methoxamine)
2. α-agonists (phenylephrine)
3. β-agonists (isoprotenerol)

Indirect „potentiating effect”
1. cause release of NE (ephedrine, amphetamine, metamphetamine)
2. block NE reuptake (cocaine)

Question 29

V. Pharmacology
1. Examples of Drugs that block adrenergic activity

Answer 29

• Direct
  1. α-blockers (phentolamine, prazosin)
  2. β-blockers (propranolol, atenolol)
• Indirect
  Block synthesis, storage and release of NE (reserpine, guanethidine)