O

PI 4,5-bisphosphate

PI 4,5-bisphosphate

1,2-Diacylglycerol (DAG)

1,2-Diacylglycerol (DAG)

Inositol 1,4,5-trisphosphate

Inositol 1,4,5-trisphosphate

▲ FIGURE 13-28 Synthesis of DAG and IP3 from membrane-bound phosphatidylinositol (PI). Each membrane-bound PI kinase places a phosphate (yellow circles) on a specific hydroxyl group on the inositol ring, producing the phosphoinositides

PIP and PIP2. Cleavage of PIP2 by phospholipase C (PLC) yields the two important second messengers DAG and IP3. [See A. Toker and L. C. Cantley, 1997, Nature 387:673, and C. L. Carpenter and L. C. Cantley, 1996, Curr. Opin. Cell Biol. 8:153.]

Inositol 1,4,5-Trisphosphate (IP3) Triggers Release of Ca2+ from the Endoplasmic Reticulum

Most intracellular Ca2+ ions are sequestered in the mitochondria and in the lumen of the endoplasmic reticulum (ER) and other vesicles. Cells employ various mechanisms for regulating the concentration of Ca2+ ions in the cytosol, which usually is kept below 0.2 ^M. For instance, Ca2+ ATPases pump cyto-solic Ca2+ ions across the plasma membrane to the cell exterior or into the lumens of intracellular Ca2+-storing compartments (see Figure 7-7). As we discuss below, a small rise in cytosolic Ca2+ induces a variety of cellular responses, and thus the cytosolic concentration of Ca2+ is carefully controlled.

Binding of many hormones to their cell-surface receptors on liver, fat, and other cells induces an elevation in cytosolic Ca2+ even when Ca2+ ions are absent from the surrounding extracellular fluid. In this situation, Ca2+ is released into the cytosol from the ER lumen through operation of the IP3-gated Ca2+ channel in the ER membrane. This large protein is composed of four identical subunits, each containing an IP3-binding site in the N-terminal cytosolic domain. IP3 binding induces opening of the channel, allowing Ca2+ ions to exit from the ER into the cytosol (Figure 13-29). When various phosphorylated inositols found in cells are added to preparations of ER vesicles, only IP3 causes release of Ca2 + ions from the vesicles. This simple experiment demonstrates the specificity of the IP3 effect.

The IP3-mediated rise in the cytosolic Ca2+ level is only transient because Ca2+ ATPases located in the plasma mem brane and ER membrane actively pump Ca2+ from the cytosol to the cell exterior and ER lumen, respectively. Furthermore, within a second of its generation, one specific phosphate on IP3 is hydrolyzed, yielding inositol 1,4-bisphosphate, which does not stimulate Ca2+ release from the ER.

Without some means for replenishing depleted stores of intracellular Ca2 + , a cell would soon be unable to increase the cytosolic Ca2+ level in response to hormone-induced IP 3. Patch-clamping studies have revealed that a plasmamembrane Ca2+ channel, called the TRP channel or the store-operated channel, opens in response to depletion of ER Ca2+ stores (see Figure 13-29). In a way that is not understood, depletion of Ca2+ in the ER lumen leads to a conformational change in the IP3-gated Ca2+ channel that allows it to bind to the TRP Ca2+ channel in the plasma membrane, causing the latter to open. Indeed, expression in cells of a specific fragment of the ER membrane IP3-gated Ca2+ channel prevents opening of the TRP channel upon depletion of ER Ca2+ stores, implicating an interaction between the two Ca2+ channels in opening the TRP channel.

Opening of IP3-gated Ca2+ channels is potentiated by cytosolic Ca2+ ions, which increase the affinity of these channel receptors for IP3, resulting in greater release of stored Ca2 + . Higher concentrations of cytosolic Ca2 + , however, inhibit IP3-induced release of Ca2+ from intracellular stores by decreasing the affinity of the receptor for IP3. This complex regulation of IP3-gated Ca2+ channels in ER membranes by cytosolic Ca2+ can lead to rapid oscillations in the cytosolic Ca2+ level when the IP3 pathway in cells is stimu-

Store-operated 0 0

Ca2+

Phospholipase C

Exterior

Plasma membrane

Cytosol

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