Vesicles epinephrine

The vesicular monoamine transporters (VMATs) were identified in a screen for genes that confer resistance to the parkinsonian neurotoxin MPP+ [2]. The resistance apparently results from sequestration of the toxin inside vesicles, away from its primary site of action in mitochondria. In addition to recognizing MPP+, the transporter s mediate the uptake of dopamine, ser otonin, epinephrine, and norepinephrine by neurons and endocrine cells. Structurally, the VMATs show no relationship to plasma membrane monoamine transporters. 

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. 

Synthesis of noradrenaline (norepinephrine) is shown in Figure 4.7. This follows the same route as synthesis of adrenaline (epinephrine) but terminates at noradrenaline (norepinephrine) because parasympathetic neurones lack the phenylethanolamine-N-methyl transferase required to form adrenaline (epinephrine). Acetylcholine is synthesized from acetyl-Co A and choline by the enzyme choline acetyltransferase (CAT). Choline is made available for this reaction by uptake, via specific high-affinity transporters, within the axonal membrane. Following their synthesis, noradrenaline (norepinephrine) or acetylcholine are stored within vesicles. Release from the vesicle occurs when the incoming nerve impulse causes an influx of calcium ions resulting in exocytosis of the neurotransmitter. 

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. 

Several of the neurotransmitters are small-molecule amines such as dopamine, serotonin, epinephrine, and norepinephrine. These neurotransmitters are synthesized in the cytoplasm of the axon terminal and subsequently transported into and stored within the synaptic vesicles. The amino acids glycine and glutamic acid are normal constituents of proteins and are present in abundance in the axons. These are also stored in synaptic vesicles. Each electrical impulse that arrives at the presynaptic side of a synapse will cause only a small minority of the synaptic vesicles to fuse with the plasma membrane and discharge their contents. The remaining synaptic vesicles remain, waiting for subsequent electrical impulses. At the same time, neurotransmitter synthesis continues, as does their storage in synaptic vesicles. This tends to restore the full complement of amine neurotransmitters at the axon terminal. 

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. 

It is important to make a clear distinction between neuronal and vesicular transport. Neuronal transport occurs from the junctional extracellular fluid (biophase) across the cell membrane of the neuron and into the neuronal cytosol. Vesicular transport is from the neuronal cytosol across the membrane of the vesicle and into the vesicle. Although these two systems readily transport both norepinephrine and epinephrine, certain drugs will selectively inhibit one or the other transport system. 

Dopamine, abbreviated DA, is a biosynthetic compound and neurotransmitter produced in the body from the amino acid tyrosine by several pathways. It is synthesized in the adrenal gland where it is a precursor to other hormones (see Epinephrine) and in several portions of the brain, principally the substantia nigra and hypothalamus. Dopamine is stored in vesicles in the brain s presynaptic nerve terminals. It is closely associated with its immediate precursor, L-Dopa (levodopa). Casmir Funk (1884—1967) first synthesized Dopa in racemic form... 

Cyclic AMP is eventually eliminated by cAMP phosphodiesterase, and Gs turns itself off by hydrolysis of its bound GTP to GDP. When the epinephrine signal persists, j8-adrenergic receptor-specific protein kinase and arrestin 2 temporarily desensitize the receptor and cause it to move into intracellular vesicles. In some cases, arrestin also acts as a scaffold protein, bringing together protein components of a signaling pathway such as the MAPK cascade. 

Catecholamines produced in the brain and in other neural tissues function as neurotransmitters, but epinephrine and norepinephrine are also hormones, synthesized and secreted by the adrenal glands. Like the peptide hormones, catecholamines are highly concentrated within secretory vesicles and released by exocytosis, and they act through surface receptors to generate intracellular second messengers. They mediate a wide variety of physiological responses to acute stress (see Table 23-6). 

A cell in your adrenal gland has about 2.5 X 104 tiny compartments called vesicles that contain the hormone epinephrine (also called adrenaline). 

Adrenergic neurons (Figure 6-4) also transport a precursor molecule into the nerve ending, then synthesize the catecholamine transmitter, and finally store it in membrane-bound vesicles, but—as indicated in Figure 6-5—the synthesis of the catecholamine transmitters is more complex than that of acetylcholine. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, norepinephrine is further converted to epinephrine. Conversely, synthesis terminates with dopamine in the dopaminergic neurons of the central nervous system. Several important processes in these nerve terminals are potential sites of... 

NE molecules are made inside into synaptic vesicles by the vesicular monoamine transporter (VMAT). This transport is an active, adenosine triphosphate (ATP)-requiring process. VMAT also transports DA, epinephrine and serotonin (5-HT). These hormones and transmitters are so-called monoamines (MO). Certain drugs, such as reserpine and tetrabenazine, inhibit the VMAT and suppress vesicular MO storage (Reinhard et al., 1988 Russo et al., 1994). 

Storage of norepinephrine in vesicles Dopamine is transported into synaptic vesicles by an amine transporter system that is also involved in the re-uptake of preformed norepinephrine. This carrier system is blocked by reserpine (see p. 78). Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine 3-hydroxylase. Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate and the 3-hydroxylase. Not all of the norepinephrine is packaged in vesicles some exists in a cytoplasmic pool that can be displaced. In the adrenal medulla, norepinephrine is methylated to yield epinephrine both are stored in chromaffin cells. On stimulation, the adrenal medulla releases about 85% epinephrine and 15% norepinephrine. 

Uptake of amine NTs from the neuronal cytosol into synaptic vesicles is achieved by vesicular monoamine transporters (VMAT1 and VMAT2) that sequester dopamine, epinephrine, norepinephrine and serotonin. A similar vesicle transporter (VGAT) sequesters GABA and glycine and a vesicular transporter (VAChT) sequesters acetylcholine into synaptic vesicles. 

NE is synthesized by tyrosine hydroxylation (meta ring position) followed by decarboxylation and side chain p carbon hydroxylation. The synthesis of this catecholamine is regulated by tyrosine hydroxylase. Tyrosine hydroxylation is also a key step in the synthesis of two other important catecholamines, dopamine and epinephrine. NE is packaged via active transport into synaptic (or chromaffin) vesicles prior to release by neuronal depolarization. The effects of NE are mediated by adrenergic receptors (a or P) which are G protein coupled resulting in either increases or decreases in smooth muscle tone as well as increases in cardiac rate and contractility. These effects arise out of receptor mediated increases in intracellular Ca and activation or inhibition of various protein kinases. The effects of NE are terminated essentially as a result of its active transport into the presynaptic nerve ending via an energy and Na" dependent process which utilizes the norepinephrine transporter (NET). Ultimately, NE and other catecholamines are metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). 

Schuldiner S, Fishkes H, Kanner Bl (1978) Role of a transmembrane pH gradient in epinephrine transport by chromaffin granule membrane vesicles. Proc. Natl. Acad. Sci. 75 3713-3716. 

Catecholamines are stored in several types of vesicular granules that differ in size and type of protein and peptide components. In rat and bovine adrenal medulla there are two populations of chromaffin cells with morphologically distinct vesicles that preferentially store either norepinephrine or epinephrine and that release the two catecholamines differentially in response to different stimuli. In sympathetic nerves there are large and small dense core vesicles, the latter believed to be formed by retrieval of membranes of large dense core vesicles after exocytosis. ... 

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