2005A07 Outline the main biochemical events involved in noradrenergic transmission.
Outline how these may be altered by the use of monoamine oxidase inhibitors.

List:

· Synthesis

· Nerve pathway

· Nerve terminal

· Receptor activity

· MAOi effect

Synthesis:

Nerve pathway:

At the nerve terminal:

· NAd synthesized

· Transport into vesicles by vesicular monoamine transporter (VMAT)

· Action potential -> ↑Ca²⁺ influx via L-Ca²⁺ -> exocytosis

· Reuptake by norepinephrine transporter (NET)

· Again transported into vesicles; or

· Degradation by COMT to normetadrenaline; or

· Degradation by COMT and MAO to vanillylmandelic acid
 (VMA)

Receptor activation:

β1	· e.g. myocardium · Gs G protein coupled receptor (GPCR) · ↑activity adenylyl cyclase -> ↑cAMP -> ↑activation PKA · Phosphorylation of multiple targets
β2	· e.g. airway smooth muscle · Gs GPCR · ↑activity adenylyl cyclase -> ↑cAMP -> ↓MLCK activity
α1	· e.g. vascular smooth muscle · Gq GPCR -> ↑cleavage PIP2 -> ↑IP3 and ↑Ca^2+, and ↑DAG

MAOi interference:

MAOi	· MAO-A: degrades mainly noradrenaline, serotonin, dopamine · MAO-B: degrades mainly serotonin, tryptamine · Effect: ↑monoamines at nerve terminals
MAOi drug interactions	· Indirect acting sympathomimetics e.g. ephedrine -> ↑↑↑effect (hypertensive crisis) · Serotonin reuptake inhibitors: ↑↑effect (serotonin syndrome)