Catecholamines vesicles

Antihypertensive (rarely used) selective inhibitor of vesicle catecholamine-H antiporter used in HTN, causes depletion of catecholamines and 5-HT from their stores. Tox severe depression, suicide, ulcers. 

Together with dopamine, adrenaline and noradrenaline belong to the endogenous catecholamines that are synthesized from the precursor amino acid tyrosine (Fig. 1). In the first biosynthetic step, tyrosine hydroxylase generates l-DOPA which is further converted to dopamine by the aromatic L-amino acid decarboxylase ( Dopa decarboxylase). Dopamine is transported from the cytosol into synaptic vesicles by a vesicular monoamine transporter. In sympathetic nerves, vesicular dopamine (3-hydroxylase generates the neurotransmitter noradrenaline. In chromaffin cells of the adrenal medulla, approximately 80% of the noradrenaline is further converted into adrenaline by the enzyme phenylethanolamine-A-methyltransferase. 

The pathway for synthesis of the catecholamines dopamine, noradrenaline and adrenaline, illustrated in Fig. 8.5, was first proposed by Hermann Blaschko in 1939 but was not confirmed until 30 years later. The amino acid /-tyrosine is the primary substrate for this pathway and its hydroxylation, by tyrosine hydroxylase (TH), to /-dihydroxyphenylalanine (/-DOPA) is followed by decarboxylation to form dopamine. These two steps take place in the cytoplasm of catecholaminereleasing neurons. Dopamine is then transported into the storage vesicles where the vesicle-bound enzyme, dopamine-p-hydroxylase (DpH), converts it to noradrenaline (see also Fig. 8.4). It is possible that /-phenylalanine can act as an alternative substrate for the pathway, being converted first to m-tyrosine and then to /-DOPA. TH can bring about both these reactions but the extent to which this happens in vivo is uncertain. In all catecholamine-releasing neurons, transmitter synthesis in the terminals greatly exceeds that in the cell bodies or axons and so it can be inferred... 

Large, non-lipid-soluble molecules may cross the capillary wall by transcytosis. This mechanism involves the transport of vesicles from one side of the capillary wall to the other. Many hormones, including the catecholamines and those derived from proteins, exit the capillaries and enter their target tissues by way of transcytosis. 

Reith M., Kramer H., Sershen H., Lajtha A. Cocaine completely inhibits catecholamine uptake into brain synaptic vesicles. Res. Commun. Subst. Abuse. 10 205, 1989. 

Sensitive electrochemical techniques have also been developed to directly measure the release of oxidizable neurotransmitters such as catecholamines (CAs) and serotonin (5-hydroxytryptamine, 5-HT). Current flows in the circuit when the potential of the electrode is positive enough to withdraw electrons from, i.e. oxidize, the released neurotransmitter. The technique is very sensitive and readily detects the release of individual quanta of neuro transmitter resulting from the fusion of single secretory vesicles to the plasmalemma (Fig. 10-2). 

Catecholamines are concentrated in storage vesicles that are present at high density within nerve terminals 213... 

Ordinarily, low concentrations of catecholamines are free in the cytosol, where they may be metabolized by enzymes including monoamine oxidase (MAO). Thus, conversion of tyrosine to l-DOPA and l-DOPA to dopamine occurs in the cytosol dopamine then is taken up into the storage vesicles. In norepinephrine-containing neurons, the final P-hydroxylation occurs within the vesicles. In the adrenal gland, norepinephrine is N-methylated by PNMT in the cytoplasm. Epinephrine is then transported back into chromaffin granules for storage. 

The action of catecholamines released at the synapse is modulated by diffusion and reuptake into presynaptic nerve terminals. Catecholamines diffuse from the site of release, interact with receptors and are transported back into the nerve terminal. Some of the catecholamine molecules may be catabolized by MAO and COMT. The cate-cholamine-reuptake process was originally described by Axelrod [18]. He observed that, when radioactive norepinephrine was injected intravenously, it accumulated in tissues in direct proportion to the density of the sympathetic innervation in the tissue. The amine taken up into the tissues was protected from catabolic degradation, and studies of the subcellular distribution of catecholamines showed that they were localized to synaptic vesicles. Ablation of the sympathetic input to organs abolished the ability of vesicles to accumulate and store radioactive norepinephrine. Subsequent studies demonstrated that this Na+- and Cl -dependent uptake process is a characteristic feature of catecholamine-containing neurons in both the periphery and the brain (Table 12-2). 

P cells of the pancreatic islets in combination with atoms of zinc, but when required to regulate blood glucose concentration, the prohormone is cleaved and functional insulin is released into the circulation along with the C-peptide. This example of post-translational processing is mediated by peptidases which are contained in the vesicles along with the proinsulin. The fusion of the secretory vesicles with the cell membrane and activation of the peptidase prior to exocytosis of the insulin are prompted by an influx of calcium ions into the P-cell in response to the appropriate stimulus. Similarly, catecholamines are synthesized and held within the cell by attachment to proteins called chromogranins. 

In contrast, much is known about the catabolism of catecholamines. Adrenaline (epinephrine) released into the plasma to act as a classical hormone and noradrenaline (norepinephrine) from the parasympathetic nerves are substrates for two important enzymes monoamine oxidase (MAO) found in the mitochondria of sympathetic neurones and the more widely distributed catechol-O-methyl transferase (COMT). Noradrenaline (norepinephrine) undergoes re-uptake from the synaptic cleft by high-affrnity transporters and once within the neurone may be stored within vesicles for reuse or subjected to oxidative decarboxylation by MAO. Dopamine and serotonin are also substrates for MAO and are therefore catabolized in a similar fashion to adrenaline (epinephrine) and noradrenaline (norepinephrine), the final products being homo-vanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) respectively. 

It now seems clear that stores of catecholamines in postganglionic sympathetic nerve pre-synaptic vesicles can, for the purposes of the present discussion, be divided into two types ... 

Reserpine causes a breakdown of norepinephrine, dopamine, and serotonin in neuron endings. It weakens intracellular uptake of biogenic amines and reduces the ability if storing them in vesicles. It is possible that reserpine acts on membrane vesicles, irreversibly inhibiting ATP-Mg (adenosinetriphosphate) requiring process that is responsible for the uptake of biogenic amines in intemeuronal vesicles. Breakdown of catecholamines is expressed by a decreased number of intraneuronal serotonin and dopamine. 

The adrenal medulla synthesizes two catecholamine hormones, adrenaline (epinephrine) and noradrenaline (norepinephrine) (Figure 1.8). The ultimate biosynthetic precursor of both is the amino acid tyrosine. Subsequent to their synthesis, these hormones are stored in intracellular vesicles, and are released via exocytosis upon stimulation of the producer cells by neurons of the sympathetic nervous system. The catecholamine hormones induce their characteristic biological effects by binding to one of two classes of receptors, the a- and )S-adrenergic receptors. These receptors respond differently (often oppositely) to the catecholamines. 

Octopamine (4.41), which carries a p-hydroxyl group, is taken up even more readily into storage vesicles and is, in turn, released when the neuron fires. As an adrenergic agonist, octopamine is, however, only about one-tenth as active as NE therefore, it acts as a very weak neurotransmitter. Compounds such as this behave like neurotransmitters of low potency, and are called false transmitters. On the other hand, octopamine may be a true transmitter in some invertebrates, with receptors that cannot be occupied either by other catecholamines or by serotonin. 

Dopamine metabolism was covered in the discussion of general catecholamine biochemistry. Dopamine is stored in synaptic vesicles, and this storage can be manipulated. Although the reuptake of released DA is the major deactivating mechanism, MAO and COMT act enzymatically on DA in the same way as on NE. However, following the degradative pathway of NE, DA will finally be metabolized to homovanillic acid (3-methoxy-4-hydroxy-phenylacetic acid), since it lacks the P-hydroxyl group. 

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