Chromaffin granule transporter

Much of the early work on these transporters was carried out on the chromaffin granules of the bovine adrenal medulla. These studies revealed the transporter to be a polypeptide of 80kDa. However, two VMATs have now been characterised and these are the products of different genes. Evidence suggests that both have 12... 

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 principal mechanism for the deactivation of released catecholamines is, however, not enzymatic destmction but reuptake into the nerve ending. The presynaptic membrane contains an amine pump—a saturable, high-affinity, Na" -dependent active-transport system that requires energy for its function. The recycled neurotransmitter is capable of being released again, as experiments with radiolabelled [ H]NE have shown, and can be incorporated into chromaffin granules as well. Many drugs interfere with neurotransmitter reuptake and metabolism, as discussed in subsequent sections. 

Darchen F, Scherman D, Henry JP (1989) Reserpine binding to chromaffin granules suggests the existence of two conformations of the monoamine transporter. Biochemistry 28 1692-1697. 

Johnson RG, Jr. (1988b) Accumulation of biological amines into chromaffin granules a model for hormone and neurotransmitter transport. Physiol Rev 68 232-307. 

Knoth J, Zallakian M, Njus D (1981) Stoichiometry of H+-linked dopamine transport in chromaffin granule ghosts. Biochemistry 20 6625-6629. 

Peter D, Jimenez J, Liu Y, Kim J, Edwards RH (1994) The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors. J Biol Chem 269 7231-7237. 

Rudnick G, Steiner-Mordoch SS, Fishkes H, Stern-Bach Y, Schuldiner S (1990) Energetics of reserpine binding and occlusion by the chromaffin granule biogenic amine transporter. Biochemistry 29 603-608. 

Sagne C, Isambert MF, Vandekerckhove J, Henry JP, Gasnier B (1997) The photoactivatable inhibitor 7-azido-8-iodoketanserin labels the N terminus of the vesicular monoamine transporter from bovine chromaffin granules. Biochemistry 36 3345-3352. 

Weaver JA, Deupree JD (1982) Conditions required for reserpine binding to the catecholamine transporter on chromaffin granule ghosts. Eur J Pharmacol 80 437 438. 

Johnson RG Jr. (1988) Accumulation of biological amines into chromaffin granules a model for hormone and neurotransmitter transport. Physiol Rev 68 232-307 Jorgensen AM, Tagmose L, Jorgensen AM, Bogeso KP, Peters GH (2007a) Molecular dynamics simulations of Na-l-/Q(-)-dependent neurotransmitter transporters in a membrane-aqueous system. ChemMedChem 2 827- 40... 

The biogenesis of both acetylcholine receptor and chromaffin granules share several common properties. The specific polypeptides are synthesized and transported into the membrane by a vectorial translation process. The specific proteins are sorted out by the Golgi apparatus and eventually fuse with the plasma membrane via the secretory pathway. Yet the acetylcholine receptor functions on the plasma membrane, and therefore it should stay on this membrane for a long time (2-7 days). On the other hand, the function of chromaffin granules is to store neurotransmitters. Therefore they stay most of their lifetime inside the cell and their fusion with the plasma membrane is temporary. Soon after the secretion process, the constituents of the chromaffin granule membrane must be removed from the plasma membrane by endocytosis. 

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. 

Scherman D, Gasnier B, jaudon P et al. Hydrophobicity of the tetrabenazine-binding site of the chromaffin granule monoamine transporter. Mol Pharmacol 1988 33 72-77. 

Henry JP, Botton D, Sagne C et al. Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffine granules. J Exp Biol. 1994 196 251-262. 

Secretion of certain types of compounds into nonplasmic compartments may be followed by the passive penetration of other substances. Basic compounds may accumulate in ion traps, as do epinephrine and dopamine (D 22.1.1) in the chromaffin granules of adrenal gland cells. The driving force of the accumulation of these amines in the nonplasmic lumen of chromaffin granules is a proton gradient dependent on ATP and most probably generated by a membrane-bound ATPase. Epinephrine and dopamine in their unprotonated form easily penetrate the membranes of the chromaffin granules and are trapped in the vesicles in their protonated form (Fig. 4). Probably the same mechanism is involved in accumulation of certain alkaloids in plant cells. Nicotine, for instance, in Nicotiana rustica is synthesized mainly in the roots. It is released from the root cells, transported to the aerial parts in the stream of water driven by transpiration, and accumulated, probably in the protonated form, in several nonplasmic compartments of the leaf cells. 

Although the midpoint reduction potential for the pair ascorbate/AFR is -1-330 mV (pH 7), the effective reduction potential is about -1-60 mV because a low concentration of AFR is maintained by disproportionation (Njus et aL, 1990). Differences in reduction potentials of the ascorbate/AFR pair at different pH values are Important, since they drive some electron flow processes such as the transmembrane electron transport of the chromaffin granule (see section 2.3.1). 

Johnson RG, Carty SE, Scarpa A. Coupling of H gradients to catecholamine transport in chromaffin granules. Ann N Y Acad Sci 1985 456 254. 

Steiner, J.A., Hortsmann, H. and Aimers, W. (1997) Transport, docking and exocytosis of single secretory granules in live chromaffin cells. Nature, 388, 474A78. 

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