Simulation of peptide processing, compartmentation and release in neurosecretory cells

Abstract

A theoretical framework is presented which mathematically describes the transport of secretory granules in neurons and the enzymatic processing of a prohormone and subsequent intermediates within such granules. The transport system represents the synthesis of individual granules, the migration of the granules among various “diffusionally”-connected compartments, and the release of granules from designated compartmental release sites. The processing of prohormone is represented by a multiple-site cleavage reaction with separate rate constants for each cleavage site on each peptide fragment. The effects of neuron growth, processing enzyme activity decay, and changes in release probability with granule age are taken into account. Computer models were constructed based on these underlying assumptions. Simulations are used to illustrate how the distribution of peptide fragments contained in a neuron will depend on interactions of peptide processing kinetics and cellular transport and storage processes. The models provide a tool for testing how multiple cell-biological variables will interact to control the chemical mixture secreted from a peptidergic neuron.