[Frontiers in Bioscience 17, 2740-2767, June 1, 2012]

Mechanisms of dopamine quantal size regulation

Daniela B. Pereira1, David Sulzer1,2,3

1Department of Neurology, Columbia University School of Medicine, New York, NY 10032, 2 Departments of Psychiatry and Pharmacology, Columbia University School of Medicine, New York, NY 10032, 3Department of Neuroscience, New York Psychiatric Institute, New York, NY 10032

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Quantal size regulation by factors that affect DA vesicular contents
3.1. DA synthesis
3.1.1. Regulation of TH expression
3.1.2. Regulation of TH activity by phosphorylation and other post-translational modifications
3.1.3. Regulation of TH activity by protein interactions
3.1.4. Regulation of TH activity by D2 dopamine receptor activation
3.2. DA vesicular uptake and storage
3.2.1. Vesicular pH gradient
3.2.2. VMAT
3.2.2.1. Regulation of VMAT expression
3.2.2.2. Regulation of VMAT activity by G-proteins and other signaling factors
3.2.2.3. Regulation of VMAT activity by psychostimulants and D2 receptors
3.2.3. Intravesicular storage capacity
3.3. DA reuptake through DAT
3.3.1. General considerations on DAT regulation
3.3.2. Regulation of DAT by psychostimulants
3.3.3. Regulation of DAT by D2 receptors
4. Quantal size modulation by modes of vesicle fusion
4.1. Vesicle fusion modes: kiss-and-run versus full fusion
4.2. Kiss-and-run fusion: prevalence and impact on quantal release
4.3. Stimulation frequency, Ca2+ and PKC as regulators of vesicle fusion modes
4.4. Dependence of kiss-and-run on dynamin
4.5. Regulation of fusion modes by synaptic proteins
5. Other factors affecting quantal size
5.1. Intracellular factors
5.2. Extracellular factors
6. Summary and perspective
7. Acknowledgments
8. References

1. ABSTRACT

The study of dopamine (DA) quantal size, or the amount of transmitter released per vesicle fusion event, has been enabled by subsecond resolution amperometric recordings. These methods, together with other electrophysiology techniques, novel optical approaches and classical molecular biology and biochemistry methodologies, have advanced our understanding of quantal size regulation in dopaminergic and other catecholaminergic systems. The presynaptic mechanisms that determine DA quantal size regulate two features: the amount of transmitter stored in each vesicle and the fraction of vesicular contents that are released per fusion event. The amount of vesicular DA is dependent on DA synthesis, DA vesicular loading and storage and on DA reuptake from the extracellular space upon exocytosis. The mode of vesicle fusion and the related fusion pore dynamics control the fraction of DA released per fusion event. We will summarize current understanding on the regulation of these steps by endogenous and exogenous factors, including drugs of abuse and DA itself.