A two-subpopulation model that reflects heterogeneity of large dense core vesicles in exocytosis

Exocytosis of large dense core vesicles is responsible for hormone secretion in neuroendocrine cells. The population of primed vesicles ready to release upon cell excitation demonstrates large heterogeneity. However, there are currently no models that clearly reflect such heterogeneity. Here, we develop a novel model based on single vesicle release events from amperometry recordings of PC12 cells using carbon fiber microelectrode. In this model, releasable vesicles can be grouped into two subpopulations, namely, SP1 and SP2. SP1 vesicles replenish quickly, with kinetics of similar to 0.0368 s(-1), but likely undergo slow fusion pore expansion (amperometric signals rise at similar to 2.5 pA/ms), while SP2 vesicles demonstrate slow replenishment (kinetics of similar to 0.0048 s(-1)) but prefer fast dilation of fusion pore, with an amperometric signal rising rate of similar to 9.1 pA/ms. Phorbol ester enlarges the size of SP2 partially via activation of protein kinase C and conveys SP1 vesicles into SP2. Inhibition of Rho GTPase-dependent actin rearrangement almost completely depletes SP2. We also propose that the phorbol ester-sensitive vesicle subpopulation (SP2) is analogous to the subset of superprimed synaptic vesicles in neurons. This model provides a meticulous description of the architecture of the readily releasable vesicle pool and elucidates the heterogeneity of the vesicle priming mechanism.

Automated summary

Exocytosis of large dense core vesicles is crucial for hormone secretion in neuroendocrine cells. This study develops a novel model based on single vesicle release events to describe the architecture of the releasable vesicle pool and elucidate the heterogeneity of the vesicle priming mechanism.