A novel fast mechanism for GPCR-mediated signal transduction - Control of neurotransmitter release

Reliable neuronal communication depends on accurate temporal correlation between the action potential and neurotransmitter release. Although a requirement for Ca²⁺ in neurotransmitter release is amply documented, recent studies have shown that voltage-sensitive G protein-coupled receptors (GPCRs) are also involved in this process. However, how slow-acting GPCRs control fast neurotransmitter release is an unsolved question. Here we examine whether the recently discovered fast depolarization-induced charge movement in the M₂-muscarinic receptor (M₂R) is responsible for M ₂R-mediated control of acetylcholine release. We show that inhibition of the M₂R charge movement in Xenopus oocytes correlated well with inhibition of acetylcholine release at the mouse neuromuscular junction. Our results suggest that, in addition to Ca²⁺ influx, charge movement in GPCRs is also necessary for release control.