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RESEARCH-ARTICLE

Unifying concepts in stimulus-secretion coupling in endocrine cells and some implications for therapeutics

Department of Internal Medicine and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Address for reprint requests and other correspondence: S. Misler, Dept. of Internal Medicine and Dept. of Cell Biology and Physiology, Washington Univ. School of Medicine, Box 8126, St. Louis, MO 63110 (e-mail: smisler{at}dom.wustl.edu).

Abstract

Stimulus-secretion coupling (SSC) in endocrine cells remains underappreciated as a subject for the study/teaching of general physiology. In the present article, we review key new electrophysiological, electrochemical, and fluorescence optical techniques for the study of exocytosis in single cells that have made this a fertile area for recent research. Based on findings using these techniques, we developed a model of SSC for adrenal chromaffin cells that blends features of Ca²⁺ entry-dependent SSC (characteristic of neurons) with G protein receptor-coupled, Ca²⁺ release-dependent, and second messenger-dependent SSC (characteristic of epithelial exocrine cells and nucleated blood cells). This model requires two distinct pools of secretory graunules with differing Ca²⁺ sensitivities. We extended this model to account for SSC in a wide variety of peripheral and hypothalamic/pituitary-based endocrine cells. These include osmosensitive magnocellular neurosecretory cells releasing antidiuretic hormone, stretch-sensitive atrial myocytes secreting atrial natriuretic peptide, K⁺-sensitive adrenal glomerulosa cells secreting aldosterone, Ca²⁺-sensitive parathyroid chief cells secreting parathyroid hormone, and glucose-sensitive β- and -cells of pancreatic islets secreting insulin and glucagon, respectively. We conclude this article with implications of this approach for pathophysiology and therapeutics, including defects in chief cell Ca²⁺ sensitivity, resulting in the hyperparathyroidism of renal disease, and defects in biphasic insulin secretion, resulting in diabetes mellitus.

Key words: ion channels; exocytosis; granule pools; adrenal chromaffin cells; neuroendocrine cells; pancreatic islet β- and -cells