Mechanistic model for enhancement of neurotransmitter release by Aos. Arrows and blunted lines indicate activating and inhibitory processes, respectively, and a dashed line indicates inhibition by Aos. Our data support a model in which pathological Aos elicit presynaptic Ca2+entry via 7-nAChR (1) to drive insertion of an intracellular pool of ENaCs into the presynaptic membrane (2). This causes an increase in Na+influx and a resulting change in presynaptic resting membrane potential Vm, which enhances CaV2.3 VGCC opening to elevate resting [Ca2+] at the presynaptic terminal (3). This [Ca2+] increase activates protein kinase C (PKC) (4), a negative regulator of GSK-3, increasing the fraction of phosphorylated, inactive GSK-3 (5) and thereby inhibiting GSK-3-mediated negative regulation of CaV2.1 function (6). The result is increased Ca2+influx via CaV2.1 channels, with enhancement of evoked neurotransmitter release. Shading or error bars represent SEM.*p< 0.0001 and ns, non-significant.
