Adrenergic Transmission Notes

Adrenergic transmission

-released by post ganglionic sympathetic neurones which release noradrenaline from varicosities that make en passant synapses

-the target issue is inverated by multiple synaptic inputs from one fibre

-sympathetic innervations of sweat glands is an exception- as sympathetic neurons release ACH – act on muscarinic receptors

-Adrenal medulla: innervated by preganglionic sympathetic neurons, post synaptic target cells – chromaffin cells have nicotinic ACH receptors- release NA into the blood stream

-alpha receptors greater affinity to noradrenaline, B receptors have greater affinity for adrenaline

Catecholamines: Noradrenaline, adrenaline, dopamine, isoprenaline

Synthesis of noradrenaline/adrenaline

• L tyrosine, aromatic amino acid- actively taken up into adrenergic nerve varicosities by Na-dependent aromatic L-amino acid transporter

• Tyrosine hydroxylase (cytoplasmic enzyme that is loosely attached to the endoplasmic reticulum) catalyses the conversion of tyrosine to L-dihydroxyphenylalanine (L-DOPA). The cofactors for this enzyme are Fe ²⁺ and tetrahydropteridine.The Km (affinity) is close to plasma concentration = 0.1mmol/L.

- The 1^st hydroxylation step is the main control point for noradrenaline synthesis. Tyrosine hydroxylase inhibited by noradrenaline-end product of the biosynthetic pathway-Sympathetic nerve activity increases, synthesis increases-noradrenline competes for the biopterin binding site and reduces the tyrosine hydroxylase

-it is also inhibited by phosphorylation.

α-mehtyltryosine- competitive inhibitor of tyrosine hydroxylase, reduces the amount of NT

• DOPA is converted into dopamine (neurotransmitter in the brain, gut and kidneys) by dopa decarboxylase

  • Carbidopa- peripheral inhibitor (doesn’t cross blood brain barrier) used in parkinson’s treatment to increase amount of L-Dopa

• Dopamine is then transported into synaptic vesicles by vesicular monoamine transporter--reserpine- binds to the amine binding site of the vesicular monoamine transporter and blocks the uptake of dopamine and depletes the store of noradrenaline- used as anti-hypertensive and acts in the periphery and brain- recovery requires new vesicles

• Dopamine B hydroxylase found in synaptic vesicles, converts dopamine into noradrenaline

  • Disulfiram-inhibits the enzyme so less noradrenaline synthesis/adrenaline synthesis

• Phenylethanolamine N-methyl transferase (PNMT)- catalyses the conversion of noradrenaline into adrenaline- located in the chromaffin cells of the adrenal medulla

-the ‘nor’ in noradrenalin means no methyl group

-catechol is a benzene with 2 0H groups, catechol amines- is a catechol with a phenylethylamine

Storage of noradrenaline

-Noradrenaline and dopamine are transported into the vesicle by vesicular monoamine transporter-2 where uptake is driven by proton gradient set up by ATP-dependent proton pump

-High concentration of noradrenaline is stored in cytoplasmic vesicles

-These are bound by loose ionic forces to ATP (ratio of 4:1 ATP) and protein chromogranin A- these substances are released with noradrenaline- the ATP binds to purinergic receptors and leads to fast excitatory synaptic potential and rapid phase of contraction

Release of noradrenaline

-preganglionic sympathetic nerve terminals release ACH- binds to nicotinic ACH receptors- excitatory synaptic potential

-action potentials leads to depolarisation and this leads to the opening of voltage gated calcium ion channels –influx of calcium ions leads to vesciles stored with noradrenaline fusing with the membrane and releasing...

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