Noradrenergic neurotransmission Flashcards
Norepinephrine
- NT in CNS and ANS
- synthesized in adrenal medulla ny chromatin cells and postganglionic sympathetic neurons
- N cells in adrenal medulla release NE
- location: heart, intestinal smooth m., blood vessels and bronchi
- stress hormone
- can suppress neuro-inflammation when release from locus coeruleus
Synthesis
tyrosine - TYROSINE HYDROXYLASE - L-DOPA - DOPA DECARBOXYLASE - dopamine - DOPAMINE B HYDROXYLASE - norepinephrine - PHENYLETHANOLAMIN N-METHYLTRANSFERASE - epinephrine
Regulation
- Rate limiting step: tyrosine hydroxylase
- negative feedback inhibition by NE
- activation by Ca2+
- phosphorylation by cAMP
- amount increased with dopamine B hydroxylase
- Steroid hormones increase activity of phenylethanolamin-N-methyltransferase
Monoamine oxidase (MAO-A and MAO-B)
- location: outer mitochondrial membrane
- most intraneuronal but some in synapse
- MAO-A break down: serotonin, melatonin, NE, E
- MAO-B break down: phenethylamine, benzylamine
- Both break down: dopamine, tyramine, tryptamine
- MAO-A inhibitors: antidepressants, antianxiety agents
Clorgilin
irreversible and selective MAO-A inhibitor
Deprenyl and Selegiline
selective MAO-B inhibitors
Catechol Oxymethyl transferase (COMT)
enzyme in NE metabolism
CH3 group from S-adenosyl methionine
localised intra and extra-neuronally
3-Methoxy-1-hydroxy-phenylglycol (MHPG)
- final product after metabolism of NE by MAO, COMT and reductase
- main metabolite in brain, appears in urine
- raised level in urine= recent sympathetic activity
- low levels = anorexia nervosa
3-methoxy-4-hydroxy mandelic acid
- metabolite of NE in PNS
- detected in urine
- raised level: peripheral sympathetic activity, tumors, pheochromocytoma
Physiological inactivation of Catecholamines
- occurs by re uptake at presynaptic nerve terminal
- inhibitors:
- cocaine: serotonine-NE-dopamine reuptake inhibitor
- SSRis: long term anti depressants
Beta1 receptors in heart: Immediate action
- cAMP dependent protein kinase
- phosphorylation of PM Ca2+ channels
- Ca2+ entry stimulates Ca2+induced Ca2+ release from SR
- rise in intracellular Ca2+
- increased force of contraction
L type Ca2+ channels in heart
Dihydropyridine DHP sensitive:
- alpha1 has 55% homology with voltage dependent Na+ channels
In the heart:
- Ca2+ entry causes Ca2+dependent Ca2+ release from SR
In striated muscle:
- a conformational change causes release from SR
Late action of beta1 receptors
- activation of SR Ca2+ATPase -> Ca2+ sequestration
- phsopholambane -> inhibits Ca2+ATPase
- cAMP dependent protein kinase activation -> phosphorylation of phospholambane -> SR Ca2+ATPase activated -> relaxation
Beta 1 receptor action in heart
PM L-Ca2+ channel:
- increased release of Ca2+ from SR by Ca2+ induced Ca2+release: POSITIVE INOTROPIC EFFECT
Phospholamban phosphorylation,increased sequestration
- POSITIVE CHRONOTROPIC EFFECT
Adipose tissue Adrenoreceptors
- B1 and B2 expressed throughout the body, B3 mostly in adipocytes
- stimulation of B-receptor: lipolysis, non-shivering thermogenesis
- B1 and B2 stimulartion - cAMP - PKA - phosphorylate HSL + perilipin - mobilization of FA
- alpha1 - Gq - glycogenolysis
- alpha2 - Gi - cAMP - inhibit lipolysis
