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 ↑Ca2+, 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)