1.10B. Sympathetic efferent mechanisms, adrenergic receptors. Flashcards
I. What are the characteristics of SYM nervous system?
- 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%)
II. Anatomy of sympathetic nervous system
1. Origin?
Thoracic Spinal Cord (T1-T12)
Lumbar (L1-L2/L3)
II. Anatomy of sympathetic nervous system
2. Ganglion?
Close to spinal cord (prevertebral and paravertebral ganglia)
II. Anatomy of sympathetic nervous system
3. Sizes of Preganglionic and Postganglionic axons
Pre - Short
Post - Long
II. Anatomy of sympathetic nervous system
4. Preganglionic Transmitter?
ACh
II. Anatomy of sympathetic nervous system
6. Postganglionic Axon Transmitter
NE
(Ach: sweat glands)
NE-NPY in GI vessels
NE- Somatostatin
NE - ATP
II. Anatomy of sympathetic nervous system
7. Receptors of the effector cells
Adrenergic receptors
α1 (IP3, Ca2+ ↑)
α2(cAMP↓)
β1 (cAMP↑)
β2 (cAMP↑)
β3 (cAMP↑)
mAChR
II. Anatomy of sympathetic nervous system
8. What are the 3 mechanisms of Elimination of Transmitters?
- NE Reuptake
- Degradation in cytoplasm
- Diffusion
II. Anatomy of sympathetic nervous system
9. What are the 3 mechanisms of Modulating Transmitter Balance?
- Membrane NE-transporter inhibition (cocaine)
- Inhibiting NE carrier in vesicle membrane
- Blocking NE synthesis
III. Adrenergic receptors
1. What are the characteristics of adrenergic receptors?
- 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)
III. Adrenergic receptors
2A. Where can you find α1 receptors (Gq)?
- Found in vascular smooth muscle of skin, skeletal muscle, and splanchnic region
- Also, in the Sphincter of GI tract and bladder
III. Adrenergic receptors
2B. What are effects of α1 receptors (Gq) on organs?
Contraction of vessels, sphincters, and radial muscle of iris
III. Adrenergic receptors
2C. Characteristics of α1 receptors (Gq)
- Activation leads to contraction!
-> Binding affinity: NE>E
III. Adrenergic receptors
2D. What is the mechanism of of α1 receptors (Gq)
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
III. Adrenergic receptors
3A. The role of α2-receptors (Gi)
Inhibition of further NE release (SYM) or ACh release (PARA)
III. Adrenergic receptors
3B. How do α2-receptors (Gi) work on sympathetic postganglionic nerve terminals?
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!)
III. Adrenergic receptors
3C. How do α2-receptors (Gi) work on parasympathetic postganglionic nerve terminals?
- will upon activation cause inhibition of release of ACh and this inhibits GI-function
- The mechanism of action involves the inhibition of adenylyl cyclase and thus decrease of cAMP levels.
III. Adrenergic receptors
4A. What are the effects of of β1-receptors (Gs) on organs?
HR ↑, conduction velocity ↑, contractility ↑, and Renin secretion↑
III. Adrenergic receptors
4B. What are the locations of of β1-receptors (Gs)?
- Prominent in the heart – present in the SA, AV nodes, and ventricular muscle.
- located in salivary glands, adipose tissue, and very importantly the kidney (promotes renin secretion.)
III. Adrenergic receptors
4C. What does Activation of β1-receptors (Gs) lead to?
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
III. Adrenergic receptors
4D. What is the mechanism of β1-receptors (Gs)?
Gs protein
-> Adenylyl cyclase -> increasing cAMP levels.
(cAMP is a second messenger for a variety of tissue-dependent stimulatory physiological activities.)
III. Adrenergic receptors
5. Characteristics of β2-receptors (Gs)
- β2-receptors (Gs) -> relaxation/dilation of vessels (E»_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!
III. Adrenergic receptors
6. The role of β3-receptors (Gs)
1/ Lipolysis in adipose tissue
2/ Thermogenesis in skeletal muscle.
III. Adrenergic receptors
7. How does sympathetic nervous system use adrenergic receptors in overall?
- 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
III. Adrenergic receptors
8. Make a summary table of Adrenergic receptors
IV. Important extra stuff
1. What are characteristics of Sympathetic adrenergic varicosities
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)
IV. Important extra stuff
2. How does Synthesis of epinephrine occur in the adrenal medulla?
- 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.
V. Pharmacology
1. Examples of Sympathomimetic drugs (sympathetic stimulation)
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)
V. Pharmacology
1. Examples of Drugs that block adrenergic activity
- Direct
1. α-blockers (phentolamine, prazosin)
2. β-blockers (propranolol, atenolol) - Indirect
Block synthesis, storage and release of NE (reserpine, guanethidine)
