The heterotrimeric G protein Go2 regulates catecholamine uptake by secretory vesicles

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Abstract
Secretory vesicles store neurotransmitters that are released by exocytosis. Their membrane contains transporters responsible for transmitter loading that are driven by an electrochemical proton gradient across the vesicle membrane. We have now examined whether uptake of noradrenaline is regulated by heterotrimeric G proteins. In streptolysin O‐permeabilized PC 12 cells, GTP‐analogues and AlF4− inhibited noradrenaline uptake, an effect that was sensitive to treatment with pertussis toxin. Inhibition of uptake was prevented by Gαo‐specific antibodies and mimicked by purified activated Gαo2. No effect was seen when Gαo2 in its inactive GDP‐bound form or purified activated Gαo1, Gαi1 and Gαi2 were tested. Down‐regulation of uptake remained unchanged when exocytosis was inhibited by the light chain of tetanus toxin. Vesicular acidification was not affected whereas binding of [3H]reserpine was reduced by GTPγS and Gαo2. These data suggest that the monoamine transporter rather than the vacuolar ATPase is affected. We conclude that catecholamine uptake is controlled by Gαo2, suggesting a novel function for heterotrimeric G proteins in the control of neurotransmitter storage.