Many cellular functions are regulated by calcium (Ca2+) signals that are generated by different signaling pathways. One of these is the inositol 1,4,5-trisphosphate/calcium (InsP3/Ca2+) signaling pathway that operates through either primary or modulatory mechanisms. In its primary role, it generates the Ca2+ that acts directly to control processes such as metabolism, secretion, fertilization, proliferation, and smooth muscle contraction. Its modulatory role occurs in excitable cells where it modulates the primary Ca2+ signal generated by the entry of Ca2+ through voltage-operated channels that releases Ca2+ from ryanodine receptors (RYRs) on the internal stores. In carrying out this modulatory role, the InsP3/Ca2+ signaling pathway induces subtle changes in the generation and function of the voltage-dependent primary Ca2+ signal. Changes in the nature of both the primary and modulatory roles of InsP3/Ca2+ signaling are a contributory factor responsible for the onset of a large number human diseases.
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