Ion Dependence of Neurotransmitter Uptake: Inhibitory Effects of Ion Substitutes

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Abstract
Several ions commonly used as substitutes for Na+ or Cl‐ were found to inhibit directly the high‐affinity uptake of norepinephrine, dopamine, serotonin, and γ‐aminobutyric acid, but not glutamate or glutamine. When Na+ was partially replaced by any of several different cations or sucrose the uptake of all neurotransmitters studied except that of serotonin was reduced more than could be accounted for by just the inhibitory effect of the cation substitute. In contrast, when Cl was partially replaced by any of several anions only the uptake of dopamine was reduced more than could be accounted for by the inhibitory effect of the anion substitute. These results suggest that for most neurotransmitters the electrochemical potential for Na+, but not for Cl, contributes to the uptake driving force. When either Na+ or Cl was totally replaced by an ion substitute or by sucrose the high‐affinity uptake was virtually abolished, an exception being that glutamate uptake was not affected when isethionate was substituted for Cl. The lack of uptake in the absence of either Na+ or Cl may reflect a specific role for these ions in either increasing the affinity between the substrate and the carrier, or facilitating the translocation process. Alternatively, the transport carriers may undergo a nonspecific conformational change to an inactive form in the absence of Na+ or Cl. A partial substitution of Na+ with Li+ or sucrose differentially affected the kinetics of uptake in that replacement with Li+, but not sucrose, usually resulted in a marked increase in the Km values. The results of this study emphasize the importance of taking into consideration the effects of ions used as substitutes in experiments undertaken to elucidate the roles of Na+ and Cl in the high‐affinity uptake of monoamine and amino acid neurotransmitters.