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Neurotransmitters of neurons and neuroendocrine cells are concentrated first in the cytosol and then in either small synaptic vesicles of presynaptic terminals or in secretory vesicles by the activity of specific transporters of the plasma and the vesicular membrane, respectively. In the central nervous system the postsynaptic response depends—amongst other parameters—on the amount of neurotransmitter stored in a given vesicle. Neurotransmitter packets (quanta) vary over a wide range which may be also due to a regulation of vesicular neurotransmitter filling. Vesicular filling is regulated by the availability of transmitter molecules in the cytoplasm, the amount of transporter molecules and an electrochemical proton-mediated gradient over the vesicular membrane. In addition, it is modulated by vesicle-associated heterotrimeric G proteins, Gαo2 and Gαq. Gαo2 and Gαq regulate vesicularmonoamine transporter (VMAT) activities in brain and platelets, respectively. Gαo2 also regulates vesicular glutamate transporter (VGLUT) activity by changing its chloride dependence. It appears that the vesicular content activates the G protein, suggesting a signal transduction from the luminal site which might be mediated by a vesicular G protein-coupled receptor or as an alternative possibility by the transporter itself. Thus, G proteins control transmitter storage and thereby probably link the regulation of the vesicular content to intracellular signal cascades. [ABSTRACT FROM AUTHOR]