Regulation of exocytosis in neuroendocrine cells: spatial organization of channels and vesicles, stimulus-secretion coupling, calcium buffers and modulation

Neuroendocrine cells display a similar calcium dependence of release as syn apses but a strongly different organization of channels and vesicles. Bioph ysical and biochemical properties of large dense core vesicle release in ne uroendocrine cells suggest that vesicles and channels are dissociated by a distance of 100-300 nm. This distinctive organization relates to the sensit ivity of the release process to mobile calcium buffers, the resulting relat ionship between calcium influx and release and the modulatory mechanisms re gulating the efficiency of excitation-release coupling. At distances of 100 -300 nm, calcium buffers determine the calcium concentration close to the v esicle. Notably, the concentration and diffusion rate of mobile buffers aff ect the efficacy of release, but local saturation of buffers, possibly enha nced by diffusion barriers, may limit their effects. Buffer conditions may result in a linear relationship between calcium influx and exocytosis, in s pite of the third or fourth power relation between intracellular calcium co ncentration and release. Modulation of excitation-secretion coupling not on ly concerns the calcium channels, but also the secretory process. Transmitt er regulation mediated by cAMP and PKA, as well as use-dependent regulation involving calcium, primarily stimulates filling of the releasable pool. In addition, direct effects of cAMP on the probability of release have been r eported. One mechanism to achieve increased release probability is to decre ase the distance between channels and vesicles. GTP may stimulate release i ndependently from calcium. Thus, while in most cases primary inputs trigger ing these pathways await identification, it is evident that large dense cor e vesicle release is a highly controlled and flexible process. (C) 2000 Els evier Science B.V. All rights reserved.