Kupchik et al. reveal how shape-shifting synaptic receptors help set neurotransmitters free.

Researchers have known for more than 50 years that calcium controls neurotransmitter release. When an action potential reaches the synapse, calcium rushes into the pre-synaptic neuron, prompting it to rapidly unload neurotransmitters. But several lines of evidence suggest that calcium gets assistance from G protein–coupled receptors (GPCRs) at pre-synaptic nerve endings. The receptors' best known job in synapses is adjusting the amount of acetylcholine and other neurotransmitters that the neuron discharges. Because this task takes seconds or even minutes to perform, how GPCRs regulate a process that occurs in milliseconds is unclear. Four years ago, the researchers furnished a possible answer, discovering that the arrival of the action potential at the synapse spurs “charge movements” in GPCRs. Charged amino acids in the proteins change position, altering the receptors' shape.

To determine whether these molecular twitches help unleash neurotransmitters, the researchers used the compound carbachol to inhibit charge movements in the M2R receptor, which governs the release of acetylcholine. Kupchik et al. could apply carbachol at precise times with a flash of UV light, which liberates a caged version of the molecule. The team found that blocking charge movements just before or during the action potential cut neurotransmitter release. But adding the inhibitor just afterward had no effect.

The researchers suggest GPCRs serve as a brake that prevents neurotransmitter vesicles from merging with the presynaptic membrane. When an action potential reaches the synapse, the receptors change shape, removing this inhibition. Thus, GPCR charge movements dictate the timing of neurotransmitter release, whereas calcium spurs exocytosis. The researchers now want to determine whether the same mechanism works for other neurotransmitters, such as glutamate.

et al
J. Cell Biol.