Multiple mechanisms for enhancement transmitter release. A, A schematic drawing to illustrate the two mechanisms that can enhance transmitter release. The solid curve in the upper panel represents the time course of vesicular release activated by a 20 msec presynaptic pulse (lower trace, solid line). Transmitter release can be increased by accelerating release kinetics (wide-spaced dotted line and α↑) and/or by increasing the total number of vesicles released without altering release kinetics (dashed line and V↑). A brief presynaptic depolarization with a duration of 2.5 msec (lower trace, dashed line) allows one to observe only the beginning of transmitter release and therefore does not provide sufficient resolution to observe the mechanisms underlying release (double arrows). Inset, The transmitter release process is modeled according to a simple reaction in whichV represents the concentration of available vesicles andR represents release; the secretion step has a forward reaction rate of α, which is modulated by calcium ions.B, Block diagram illustrating different mechanisms that could increase transmitter output and the relationship between activity-dependent and modulator-mediated synaptic enhancement. 5-HT and OA are both able to increase protein phosphorylation. Physiological effects of protein phosphorylation include an acceleration in release kinetics and an increase in total release. Both mechanisms result in an increase in action potential-activated release. Facilitation processes have access only to the kinetic branch of the flow chart. It remains unclear whether the increase in [Ca⁺²]_i associated with F2 facilitation accelerates release kinetics by way of protein phosphorylation (dotted arrow) or processes further downstream (dashed arrow).