We have recently proposed a mechanism to describe secretion, a fundament process in all cells. That hypothesis, called porocytosis, embodies all available data, and encompasses both forms of secretion, i.e., vesicular and constitutive. The current accepted view of exocytotic secretion involves the physical fusion of vesicle- and plasma membranes. However, that hypothesized mechanism does not fit all available physiological data (Silver et al., 2001; Kriebel et al., 2001). Energetics of apposed lipid bilayers do not favor unfacilitated fusion. Calcium ion levels are elevated in microdomains at levels of 10(-4)-10(-3)M for 1 ms or less, with the calcium ions showing limited lateral mobility at the site of secretion (Llinas et al., 1992, Silver et al., 1994). We consider that calcium ions, whose mobility is restricted in space and time, establish "salt-bridges" among adjacent lipid molecules, and establishes transient pores that span the vesicle and plasma membrane lipid bilayers; the lifetime of that transient pore being completely dependent on duration of sufficient calcium ion levels.
We believe that there is sufficient experimental evidence to support the premise that transmitter is secreted by the simultaneous activation of arrays of fusion pores at docked vesicles. This process is initiated by the action potential that activates calcium channels to increase the number of cytoplasmic calcium ions. Calcium ions trigger fusion pores to flicker open causing transmitter to diffuse from vesicular stores. We define the term porocytosis to identify this process and use the term synaptomere to indicate the anatomical and physiological functional unit of the synapse or junction. Our model shows that the simultaneous flicker of fusion pores in an array can generate unitary-end plate potentials (u-EPPs) and miniature end plate potentials (MEPPs) and that activation of all fusion pores produces EPPs. U-EPPs and EPPs generated with the model show mean values and coefficients of variation similar to experimental observations. The model is robust in that the number of docked vesicles can vary and these can be full to empty depending on nerve frequencies and vesicular traffic. The model shows that the overall process of excitation-secretion coupling is highly deterministic. At the neuromuscular junction, secretion from arrays of fusion pores ensures that a muscle fiber action potential is always produced over a range of frequencies because all transmitter release sites are activated. Our model shows that transmission at the synaptomere guarantees fidelity of information transfer at different frequencies. This characteristic shows a dynamic relationship of the secretory process to memory and learning.
The porocytosis hypothesis is based on the arrayed nature of synaptic vesicles which forms the anatomical functional unit of secretion. The presynaptic array and the postsynaptic array of receptors form a synaptomere which is the unit of transmission. A transient increase in calcium ions, triggered by an action potential, activates all pores of the array to pulse transmitter. The array insures transmission while permitting a frequency dependent amount of secretion. Therefore the amount of secretion is variable which permits plasticity. Secretion from the array has the property of immediate synaptic plasticity whereas a change in array size would change synaptic strength. The robust nature of the array insures fidelity of transmission, a frequency dependent dynamic signature of transmission giving the property of immediate plasticity; and, a change in array size yields a change in synaptic strength for long term reliability.
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