After reading this article you will learn about the synthesis of catecholamines.
Norepinephrine (NE) or noradrenaline (NA) is the main transmitter at sympathetic neuro-effector junctions (except sweat glands and hair follicles) and CNS. Other neurotransmitters related to adrenergic transmission are dopamine (predominant in brain) and epinephrine (secreted by adrenal medulla). They are commonly named as catecholamines due to presence of catechol nucleus in their structures.
Synthesis storage and release of Catecholamines:
Catecholamines are synthesised from the amino acid. Phenylalanine in stepwise Process (Table 16.5).
The conversion of tyrosine to DOPA is the “rate-limiting step” in the synthesis of catecholamines. α-Methyl-p-tyrosine (AMPT) strongly inhibits tyrosine hydroxylase enzyme to block the synthesis of successors. α-Methyldopa, an inhibitor of L-aromatic amino acid (DOPA) decarboxylase, is decarboxylated and then hydroxylated to form α-methyl-norepinephrine, in place of norepinephrine, which acts as a “false neurotransmitter.”
Copper chelating agents and disulfirum inhibit dopamine- β- hydroxylase and cause a partial depletion of NE store. When NE concentration in the axoplasm is increased, a feedback inhibition of tyrosine hydroxylase is caused by NE to regulate the catecholamine synthesis. After synthesis, NE is stored within the synaptic vesicles or granules till it is required to be released.
In adrenal medulla, NE formed within the chromaffin granules diffuses into the cytoplasm and methylated to adrenaline which is again taken up by separate granules and stored there. An action potential causes influx of Ca2+ through the terminal axonal membrane, with subsequent fusion between the vesicle and the nerve membrane resulting in exocytosis of NE.
The NE release is controlled by auto-inhibitory feedback by NE through pre-junctional membranous α2 receptors. Epinephrine is secreted from adrenal medulla by stimulation of cholinergic system. Dopamine is released from the dopaminergic nerve endings of CNS.
Action and Termination of Catecholamines:
The released NE or epinephrine activates α and β receptors on the effector cell membrane. There are two main α-adrenoceptor subtypes (α1 and α2) and three β-adrenoceptor subtypes (β1, β2 and β3). They are all coupled with the G-proteins.
After binding of agonists, receptors activate phospholipase C, thus producing IP3 (stimulate release of Ca2+ from endoplasmicreticulum) and DAG (stimulate protein kinase C) as second messengers. a2 receptors inhibit adenylyl cyclase (decrease cAMP formation) and all β receptor subtypes stimulate adenylyl cyclase (produce cAMP and thereby activate cAMP-dependent protein kinase A).
Epi → Epinephrine, NE → Norepinephrine, Iso – Isoproterenol, JG → Juxtaglomerular, VSM → Vascular smooth muscle, GISM → Gastrointestinal Sm. muscle, GUSM → Genitourinary, smooth muscle, SM → smooth muscles, PIL → Pancreatic islets of Langerhans.
Unlike cholinergic junctions there is no synaptically located enzyme that rapidly degrades catecholamines; instead, reuptake of NE by adrenergic nerve terminals and by other cells is the main mechanism of termination or inactivation of released transmitter.
Nearly 60% of the released NE reenters into the synaptic vesicles of nerve endings (uptake I), 20% is diffused into the extra-neuronal sites (uptake II), 5% binds with the receptors and about 15% of NE is destroyed by enzyme (MAO).
The two main enzymes, monoamine oxidase (MAO) and catechol-O- methyl transferase (COMT) are located intracellularly in pre and post-junctional or extra-junctional cells respectively. The axoplasmic NE is degraded by MAO whereas circulating and administered NE is mainly metabolised by COMT in liver, and to some extent in kidney and plasma.