Regulating quantal size of neurotransmitter release through a GPCR voltage sensor

Abstract

Current models emphasize that membrane voltage (Vm) depolarization-induced Ca2+ influx triggers the fusion of vesicles to the plasma membrane. In sympathetic adrenal chromaffin cells, activation of a variety of G protein coupled receptors (GPCRs) can inhibit quantal size (QS) through the direct interaction of G protein Giβγ subunits with exocytosis fusion proteins. Here we report that, independently from Ca2+, Vm (action potential) per se regulates the amount of catecholamine released from each vesicle, the QS. The Vm regulation of QS was through ATP-activated GPCR-P2Y12 receptors. D76 and D127 in P2Y12 were the voltage-sensing sites. Finally, we revealed the relevance of the Vm dependence of QS for tuning autoinhibition and target cell functions. Together, membrane voltage per se increases the quantal size of dense-core vesicle release of catecholamine via Vm → P2Y12(D76/D127) → Giβγ → QS → myocyte contractility, offering a universal Vm-GPCR signaling pathway for its functions in the nervous system and other systems containing GPCRs.

Prediction of GPCR activity using machine learning

“…G-Protein Coupled Receptors (GPCRs) are important proteins for signaling networks, such as the Ras signaling pathway and neurotransmission [1] , [2] , [3] , [4] , [5] . Through these networks the GPCR proteins regulate the physiological processes and pathogenesis of diseases associated with such signaling networks [6] , [7] , [8] .…”

Far infrared light irradiation enhances Aβ clearance via increased exocytotic microglial ATP and ameliorates cognitive deficit in Alzheimer’s disease-like mice

“…S6E and S6F), upon the Aβ stimulation, indicating that the increase in Aβ-induced extracellular ATP release of microglia treated with FIR light influences the ATP-related signal transduction. We blocked these ATP-related receptors by using suramin, a broad-spectrum antagonist of P2 purinoceptors [ 55 ], to investigate the role of extracellular ATP in the enhanced Aβ phagocytosis of microglia treated with FIR light. The results showed that suramin compromised the Aβ phagocytosis of microglia in the presence or absence of FIR light (Fig.…”

Vesicle Cholesterol Controls Exocytotic Fusion Pore

“…This shrinkage is influenced by the osmotic pressure difference between the intracellular and the extracellular solution and actin-mediated membrane tension to reel in the membrane of the fusing vesicles [77,78]. Recently, G-protein coupled receptors were also found to control the fusion pore [79]. Here we asked whether cholesterol affects the native fusion pore, in particular the sub-nanometer one [65].…”