Chromogranin A, an "on/off" switch controlling dense-core secretory granule biogenesis

We present evidence that regulation of dense-core secretory granule biogene sis and hormone secretion in endocrine cells is dependent on chromogranin A (CGA). Downregulation of CGA expression in a neuroendocrine cell line, PC1 2, by antisense RNAs led to profound loss of dense-core secretory granules, impairment of regulated secretion of a transfected prohormone, and reducti on of secretory granule proteins. Transfection of bovine CGA into a CGA-def icient PC12 clone rescued the regulated secretory phenotype. Stable transfe ction of CGA into a CGA-deficient pituitary cell line, 6T3, lacking a regul ated secretory pathway, restored regulated secretion. Overexpression of CGA induced dense-core granules, immunoreactive for CGA, in nonendocrine fibro blast CV-1 cells. We conclude that CGA is an "on/off" switch that alone is sufficient to drive dense-core secretory granule biogenesis and hormone seq uestration in endocrine cells.