Adrenergic Transmission

Question 1

adrenergic pharmacology involves the study of agents that act on pathways mediated by ____

Answer 1

• endogenous catecholamines, norepinephrine and epinephrine

*SMS is a major source of endogenous catecholamine production and release

Question 2

what are catecholamines synthesized by, what is the steps in their synthesis

Answer 2

• synthesized by chemical modifications of aa tyrosine

1. Oxidation of tyrosine to dihydroxyphenylalanine (DOPA) mediated by enzyme tyrosine hydroxylase (TH)
   
   • ​​TH is the rae limiting enzyme in the synthesis
2. DOPA is converted to dopamine by relatively nonspecific aromatic amino acid decarboxylase
3. dopamine is taken up by aynaptic vesicles where it is hydroxylated by dopamine-β -hydroxylase to yeild norepinephrine

*in tissues that produce epinephrine, norepinephrine is them methylated on its amino group by phenylethanolaine N-methyltrasnferase (PNMT)

Question 3

what is expresseion of PNMT dependent on?

Answer 3

• expression of PNMT in the adrenal medulla is largely dependent on high concentrations of the stress hormone cortisol that flows into the medulla via veins draining the adrenal cortex

*this is the enzyme methylates

Question 4

what happens once a catecholamine has exerted its effect at a postsynaptic receptor

Answer 4

• the response is terminated by one of 3 mechanisms
  1. reuptake of catacholamine into presynaptic neurons
  2. metabolism of catacholamine to an inactive metabolite

*metabolism involves two enzymes: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)

3. diffusion of cetacholamine away fromt he synaptic cleft

Question 5

what are teh two main groups of adrenergic receptors

Answer 5

α (α1, α2) and β (β1, β2, β3),

• each receptor is a member of g-protein superfamilty

Question 6

how are alpha adrenergic and β1 receptors activated

Answer 6

by both norepinephrine and epinephrine

Question 7

how are β2 receptors activated

Answer 7

• much mor responsive to epinephrine
• β2 receptors often show in adrenergic synpase diagrams as responding to norepinephine but in reality has very little effect on them

Question 8

what is the rate limiting step in the synthesis of catecholamines? What inhibits it?

Answer 8

• all synthesized from tyrosine
• rate limiting = oxidation of cytoplasmic tyrosine to dihydroxyphenylalanine (L-DOPA) catalyzed by tyrosine hydroxylase (TH)
• inhibited by

Question 9

hows does L-DOPA get converted to dopamine and put into vesicles

Answer 9

• aromatic L-amino acid decarboxylase converts L-DOPA into dopamine
• vesicular monoamine transporter (VMAT) translocated dopamine (and other monoamines) into synpatic vesicles

Question 10

how is dopamine coverted to norepinephrine in adreneric neurons

Answer 10

• in adrenergic neurons, intravesicular dopamine-β-hydorxylase converts dopamine to norepinephrine
• norepinephrine is then stores in the vesicle until release

Question 11

how is norepinephrine coverted to epinephrine

Answer 11

in adrenal mdullary cells

• norepinephrine (made form dopamine) returns to the sytosol where phenylethanolamine N-methyltransferae (PNMT) coverts norepinephrine to epinephrine
• epinephrine is then transported back into the vesicle for storage

Question 12

what happens to norepinephrine that is released

Answer 12

• can stimulate postsynaptic α1-, β1-, or β2-adrenergic receptors or presynpatic α2-adrenergic autoreceptors
• can also be taken up into presynpatic terminals by the selective NE transporter
• ME in the cytoplasm of presynpatic neuron can be futher taken up into synpatic vesicles by VMAT or degraded to 3,4- dihydoxyphenylglycoaldehyde (DOPGAL) by mitochondrion-associated monoamine oxidase (MAO)

Question 13

location and actions of the α1 receptor

Answer 13

• Smooth muscle cells (vessels in skin, mucosa and abdominal organs)
  Intestinal and urinary sphincters: contraction
• Eye: pupil dilation
• Liver: glycogenesis and glucognesis

*inc IP3/DAG = excitatory, activate PKC and calcium dependent potein kinase

Question 14

locations and actions of the α2 receptor

Answer 14

• Pancreatic β-cells: decreased insulin secretion
• Platelets: aggregation
• Nerve: decreased norepinephrine release
• Smooth muscle: contraction
• decrease cAMP: inhibitory, prevent phosphorylation of enzymes

Question 15

What are the locations and action of the β1 receptor

Answer 15

• Heart: increased rate/force of contraction
• Juxtaglomerular cells: increased renin secretion

*inc cAMP: excitatory

Question 16

Locations and actions of β2 receptor

Answer 16

• Smooth muscle (most organs and blood vessels supplying skeletal muscle): relaxation
• Liver: Glycogenesis and glycogenesis
• Skeletal muscle: Glycogenesis and K+ uptake

Question 17

Locations and actions of β3 receptor

Answer 17

adipose: lipolysis

*inc cAMP: excitatory

Question 18

impact of receptor agonists on the heart

Answer 18

M2 ‎→ decrease heart rate
β1 ‎→ increase heart rate

Question 19

impacts of agonists on (most) blood vessels

Answer 19

M3 ‎→vasodilation
α1 ‎→vasoconstriction

Question 20

impact of agonists on skeletal muscle blood vessels

Answer 20

β2 ‎→vasodilation

Question 21

impact of receptor agonists on most organ systems/glands

Answer 21

M3 ‎→ contraction ‎→ increase activity
‎ → increase secretion
β2 ‎→ relaxation of smooth muscle
α1 ‎→ constriction of sphincters

Question 22

how are autonomic drugs used in ophthamology and optometry

Answer 22

• contraction of sphincter M₃ = constriction of pupil
• contraction of dilator α1 = dilation of pupil

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