Calcium-dependent regulation of protein synthesis in intact mammalian cells.

Extensive bodies of literature describe protein synthesis and processing; the endocrinology and metabolic bases whereby a variety of hormonal, mechanical, and nutritional influences affect cell function and adaptive responses; and various regulatory mechanisms mediating concerted intracellular control. Nonetheless, our current understanding of the mechanisms responsible for the regulation and subordination of protein synthesis to the overall metabolic and stimulus-response status of the cell is inadequate. The endoplasmic reticulum is central to these concerns. Potential roles of the endoplasmic reticulum in the regulation of protein synthesis are largely unexplored. We have attempted in this rather speculative review, based largely on our own data, to project a view of the endoplasmic reticulum as moderating the rate of translation through a mechanism sensitive to sequestered Ca2+. Compensatory routes whereby cells accommodate to Ca2+ deprivation so as to resume reasonable rates of protein synthesis are seen also to focus on the endoplasmic reticulum. With additional research, the underlying relationships that exist among reticular Ca2+ storage, protein processing, and mechanisms of translational control should become more broadly evident. The prevailing view of Ca2+ as a regulator of cytosolic processes may require some extension if sequestered Ca2+ participates in biological control mechanisms emanating from the endoplasmic reticulum. In effect, a reciprocal relationship would presumably exist among processes supported by cytosolic free Ca2+ vs those promoted by sequestered stores of the cation. Speculatively, such reciprocity would allow the rapid diversion of energy from one set of processes to the other. Conceivably, chronic Ca2+ loading at sequestered sites may be related to certain cellular adaptive Ca2+ loading involving tissue hypertrophy. Potential examples of stretch-induced responses that could be cited include thickening of arteriolar smooth muscle walls in hypertension (8) and cardiac hypertrophy in aortic stenosis (46).