Human Biochemistry, Volume 2 - Murray R. 1993

Biochemistry of Intra- and Intercellular Communications
Membranes: Structure, Assembly, and Functions
Information Transfer in the Cell

Specific compounds that act as biochemical signals—such as Neurotransmitters, Hormones, and IMMUNOGLOBULINS—bind to specialized receptors (integral Proteins) exposed on the outer surface of The Cell membrane, thereby transmitting information across it into the Cytoplasm. For example, the ß-adrenergic receptor, which stereospecifically binds catecholamines, is located On the surface of target Cells. The binding of catecholamines stimulates The activity of adenylate cyclase, which is localized on the inner face of the membrane and catalyzes The formation of cAMP from ATP (Chap. 44). Thus, the information originally carried by the specific extracellular catecholamine is relayed inside, and its subsequent transmission is mediated by a second messenger, cAMP. The receptor-coupled adenylate cyclase system, containing stimulatory and inhibitory components, mediates the cellular response to many hormones, as discussed in detail in Chapter 44.

Another type of signal Transduction has recently been discovered in mammalian cells. In this signaling system, Inositol trisphosphate plays The Role of a second messenger (Fig. 42.21); its intracellular concentration is regulated by extracellular signals mediated by a transmembrane receptor. The surface of most mammalian cells features specific receptors for a diverse group of proteins known as growth factors, such as Insulin, epidermal growth factor, and platelet-derived growth factor. Upon binding of the appropriate effector molecule to the receptor, kinase activity intrinsic to the integral component of the transmembrane receptor molecule is stimulated on the cytoplasmic side of the membrane. This activity drives the phosphorylation of phosphatidylinositol to phosphatidylinositol 4-phosphate, and subsequently to phosphatidylinositol 4,5-bisphosphate. Interestingly, certain oncogenes, whose expression can lead to cell malignant transformation, also induce kinase activity that results in the formation of such polyphosphoinositides (Chap. 57).

Other cell-surface receptors, such as those for acetylcholine, antidiuretic hormone, and a₁-type catecholamines, can promote the activation of phospholipase C upon binding their respective ligands. The latter enzyme catalyzes the Hydrolysis of phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate and 1,2-diacylglycerol. Diacylglycerol is capable of activating protein kinase C, an enzyme whose activity also depends on the presence of Ca²⁺ ions in the medium. Conversely, inositol trisphosphate triggers the efficient release of calcium from intracellular stores, such as the sarcoplasmic reticulum and Mitochondria. Thus, the hydrolysis of phosphatidylinositol 4,5-bisphosphate activates protein kinase C and facilitates an increase in cytoplasmic calcium ion concentration. This activates the Na⁺, K⁺-pump, leads to a net efflux of protons from the cell, and consequently raises the intracellular pH. As a result, cell proliferation and other specific responses are triggered. In this signaling system, calcium and 1,2-diacylglycerol appear to act as third messengers. Interestingly, processes within this signaling system are modulated by certain oncogenes. They mediate phosphatidylinositol kinase activity, leading to the accumulation of polyphosphoinositides, which in turn serve as precursors for second and third messengers. Undoubtedly, other complex systems of information transfer into the cell remain to be discovered. Chapter 44 discusses the role of transmembrane signaling systems in hormone action.

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Fig. 42.21. Structure of phosphatidylinositol 4,5-bisphosphate.