ABSTRACT
Streams of action potentials or long depolarizations evoke a massive exocytosis of transmitters and peptides from the surface of dendrites, axons and cell bodies of different neuron types. Such mode of exocytosis is known as extrasynaptic for occurring without utilization of synaptic structures. Most transmitters and all peptides can be released extrasynaptically. Neurons may discharge their contents with relative independence from the axon, soma and dendrites. Extrasynaptic exocytosis takes fractions of a second in varicosities or minutes in the soma or dendrites, but its effects last from seconds to hours. Unlike synaptic exocytosis, which is well localized, extrasynaptic exocytosis is diffuse and affects neuronal circuits, glia and blood vessels. Molecules that are liberated may reach extrasynaptic receptors microns away. The coupling between excitation and exocytosis follows a multistep mechanism, different from that at synapses, but similar to that for the release of hormones. The steps from excitation to exocytosis have been studied step by step for the vital transmitter serotonin in leech Retzius neurons. The events leading to serotonin exocytosis occur similarly for the release of other transmitters and peptides in central and peripheral neurons. Extrasynaptic exocytosis occurs commonly onto glial cells, which react by releasing the same or other transmitters. In the last section, we discuss how illumination of the retina evokes extrasynaptic release of dopamine and ATP. Dopamine contributes to light-adaptation; ATP activates glia, which mediates an increase in blood flow and oxygenation. A proper understanding of the workings of the nervous system requires the understanding of extrasynaptic communication.
ABSTRACT
Neuromuscular transmission, from spontaneous release to facilitation and depression, was accurately reproduced by a mechanistic kinetic model of sequential maturation transitions in the molecular fusion complex. The model incorporates three predictions. First, calcium-dependent forward transitions take vesicles from docked to preprimed to primed states, followed by fusion. Second, prepriming and priming are reversible. Third, fusion and recycling are unidirectional. The model was fed with experimental data from previous studies, whereas the backward (ß) and recycling (ρ) rate constant values were fitted. Classical experiments were successfully reproduced with four transition states in the model when every forward (α) rate constant had the same value, and both backward rate constants were 50-100 times larger. Such disproportion originated an abruptly decreasing gradient of resting vesicles from docked to primed states. By contrast, a three-state version of the model failed to reproduce the dynamics of transmission by using the same set of parameters. Simulations predict the following: (1) Spontaneous release reflects primed to fusion spontaneous transitions. (2) Calcium elevations synchronize the series of forward transitions that lead to fusion. (3) Facilitation reflects a transient increase of priming following the calcium-dependent maturation transitions. (4) The calcium sensors that produce facilitation are those that evoke the transitions form docked to primed states. (5) Backward transitions and recycling restore the resting state. (6) Depression reflects backward transitions and slow recycling after intense release. Altogether, our results predict that fusion is produced by one calcium sensor, whereas the modulation of the number of vesicles that fuse depends on the calcium sensors that promote the early transition states. Such finely tuned kinetics offers a mechanism for collective non-linear transitional adaptations of a homogeneous vesicle pool to the ever-changing pattern of electrical activity in the neuromuscular junction.
