E

G protein adenylate cyclase

DAG IP3 cAMP

metabotropic (mGlu) glutamate receptors and second messengers

Catecholamine Neurotransmitters

Norepinephrine, a catecholamine, (called noradrenaline in the UK) is the principal neurotransmitter of the adrenergic nervous system. Epinephrine (adrenaline), another catecholamine, acts both as a neurotransmitter and a hormone. Dopamine, also a catecholamine, is an important neurotransmitter, especially in the CNS, where it is the most abundant catecholamine neurotransmitter. These neuro-chemicals bind to specific receptors, which may be ligand-gated ion channels or linked to intracellular second messenger systems.

Catecholamines are synthesized at the nerve terminal and stored in vesicles. Dietary phenylalanine is converted to ty-rosine, which is taken up into the cytoplasm of the nerve terminal and hydroxy-lated to form DOPA by tyrosine hydroxy-lase. This is the rate-limiting step of cate-cholamine biosynthesis. Tyrosine hy-droxylase requires iron, molecular O2 and tetrahydrobiopterin as cofactor. The cofac-tor helps to keep TH active in a reduced state. When NE or dopamine accumulate in the cytoplasm they inhibit the action of the cofactor. Thus the neurotransmitters control the action of TH by end-product inhibition. DOPA is converted to dopamine, which enters the vesicle and is converted to norepinephrine (NE). NE is stored in the vesicle in association with ATP, Ca2+, neuropeptide Y as cotransmitter, and a protein called chromogranin. In the adrenal medulla, NE is subsequently methylated to form epinephrine (EP). EP is also formed in several CNS nerve terminals.

NE is released from the nerve terminal when an action potential arrives and mobilizes Ca2+ stores, which enable the vesicles to fuse with the cell membrane and release the neurotransmitter into the syn-aptic cleft. The neurotransmitter diffuses across the cleft and binds to its receptors.

Catecholamine receptors occur as several different subtypes depending on the affinity for NE, EP or dopamine. The major NE/ EP subtypes are a, a2, and p2. The a, and p receptors occur predominantly post-synaptically, while the a2 receptor occurs mainly presynaptically in the CNS and acts as an autoreceptor limiting the release of NE and other neurotransmitters such as 5-HT and glutamate. Autoreceptors regulate the release of the neurotransmitter. There is now evidence that there are many different subtypes of aj and a2 receptors in the CNS, but the significance of this variation is not known.

The action of the catecholamine neuro-transmitters is terminated by their uptake into the nerve terminal by active transport, which requires ATP. This transport mechanism is called uptake 1. There is another uptake mechanism into the post-synaptic cell, called uptake 2. Once in the nerve terminal, NE may enter a vesicle or the mitochondrion where it is metabolized by monoamine oxidase (MAO). MAO is an important metabolic enzyme, found principally in neural and glial cells and in liver, glandular tissue, and the gut. There are two forms of MAO, MAO-A and MAO-B. MAO oxidizes the catecholamines to their corresponding aldehydes. The enzyme is an important target for inhibitors, the MAOI drugs, which are used to keep biological concentrations of cate-cholamines high. MAOI drugs have been used to treat clinical depression, for example. The catecholamins are metabolized also by a cytoplasmic enzyme, catechol-O-methyltransferase (COMT), which occurs in high concentrations in liver and kidney.

extracellular vesicle

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