Inositolpolyphosphate binding sites and their likely role in calcium regulation in smooth muscle

Inositol 1,4,5-trisphosphate (InsP₃) and inositol 1,3,4,5-tetrakisphosphate (InsP₄) binding sites have been identified in smooth muscle and other tissues. Subcellular localization of these receptors in smooth muscle indicates that they are present in both the sarcoplasmic reticulum membrane and the plasma membrane, although the InsP₃ receptor appears predominantly localized in the sarcoplasmic reticulum membrane. The heterogeneity of InsP₃ binding sites is confirmed by radioligand binding and molecular cloning studies. It is now clear that InsP₃, in addition to releasing intracellular Ca²⁺, can also stimulate Ca²⁺ entry across the plasma membrane. Although the mechanism of Ca²⁺ entry remains a matter for much debate, what is not in doubt is that increases in InsP₃, perhaps acting together with InsP₄, can maintain a constant influx of Ca²⁺ across the cell membrane. Compared to the InsP₃ receptor, our understanding of the InsP₄ binding site is limited. In most cases, including release of intracellular Ca²⁺ or Ca²⁺ entry, the major role of InsP₄ appears to be the potentiation of the InsP₃-induced response. Future studies of the InsP₄ binding site by purification and molecular cloning, as well as subcellular localization, are needed to clarify the role for InsP₄ in the regulation of intracellular Ca²⁺.