TY - JOUR
T1 - Structural requirements for cocaine-sensitive and -insensitive uptake of phenethylamines into the adrenal chromaffin cell
AU - Powers, Jennifer L.
AU - Plaskon, R. Richard
AU - Olsen, Greta A.
AU - May, Sheldon W.
PY - 1995/11
Y1 - 1995/11
N2 - The adrenal medullary chromaffin cell is a commonly used model for the adrenergic neuron. Although much work has been done to study the transport system in the adrenal chromaffin vesicles, relatively little is known about cellular transport, especially with regard to structural features of phenethylamines required for intracellular accumulation. We have now investigated the structural requirements of phenethylamine-related compounds for their accumulation into cultured adrenal chromaffin cells. We find that two types of cellular uptake, previously described only for dopamine, norepinephrine, and epinephrine, are also present for [3H]tyramine. Although two types of accumulation occur, tyromine accumulation occurs mainly via a cocaine-insensitive process, whereas dopamine accumulation occurs predominantly via a cocaine-sensitive process. The accumulation of [14C]- phenethylamine and p-methoxyphenethylamine is not affected by cocaine, suggesting that a ring hydroxyl substituent is necessary for cocaine- sensitive accumulation. The compounds p-hydroxyphenylpropylamine and p-hy- droxyphenyl-2-aminoethyl sulfide accumulate in the cell only via a cocaine- insensitive process, indicating that lengthening of the aminoalkyl side chain prevents cocaine-sensitive accumulation. We have performed conformational analyses of this series of compounds to determine whether the conformation of these compounds can be related to the kinetic data. For dopamine, tyramine, phenethylamine, and p-methoxyphenethylamine, two groups of energy-minimized conformers were found. We find that there is an approximately linear relationship between the K(m) values for these phenethylamines and the differences in minimized energies between the low- and highest energy conformer groups of each compound. A similar correlation was found for p- hydroxyphenyl-2-aminoethyl sulfide. These results are consistent with the hypothesis that these compounds undergo a conformational change from the low- energy conformer to the highest energy conformer before their cocaine- insensitive accumulation.
AB - The adrenal medullary chromaffin cell is a commonly used model for the adrenergic neuron. Although much work has been done to study the transport system in the adrenal chromaffin vesicles, relatively little is known about cellular transport, especially with regard to structural features of phenethylamines required for intracellular accumulation. We have now investigated the structural requirements of phenethylamine-related compounds for their accumulation into cultured adrenal chromaffin cells. We find that two types of cellular uptake, previously described only for dopamine, norepinephrine, and epinephrine, are also present for [3H]tyramine. Although two types of accumulation occur, tyromine accumulation occurs mainly via a cocaine-insensitive process, whereas dopamine accumulation occurs predominantly via a cocaine-sensitive process. The accumulation of [14C]- phenethylamine and p-methoxyphenethylamine is not affected by cocaine, suggesting that a ring hydroxyl substituent is necessary for cocaine- sensitive accumulation. The compounds p-hydroxyphenylpropylamine and p-hy- droxyphenyl-2-aminoethyl sulfide accumulate in the cell only via a cocaine- insensitive process, indicating that lengthening of the aminoalkyl side chain prevents cocaine-sensitive accumulation. We have performed conformational analyses of this series of compounds to determine whether the conformation of these compounds can be related to the kinetic data. For dopamine, tyramine, phenethylamine, and p-methoxyphenethylamine, two groups of energy-minimized conformers were found. We find that there is an approximately linear relationship between the K(m) values for these phenethylamines and the differences in minimized energies between the low- and highest energy conformer groups of each compound. A similar correlation was found for p- hydroxyphenyl-2-aminoethyl sulfide. These results are consistent with the hypothesis that these compounds undergo a conformational change from the low- energy conformer to the highest energy conformer before their cocaine- insensitive accumulation.
KW - Cell
KW - Chromaffin
KW - Cocaine-sensitive
KW - Conformational
KW - Phenethylamine
KW - Uptake
UR - http://www.scopus.com/inward/record.url?scp=0028885490&partnerID=8YFLogxK
M3 - Article
C2 - 7595487
AN - SCOPUS:0028885490
SN - 0022-3042
VL - 65
SP - 2031
EP - 2042
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -