Diacyl Glycerol Inositol Trisphosphate

FIGURE 12 Phosphatidylinositol-bisphosphate. When cleaved by phospholipase C, inositol 1,4,5 trisphosphate (IP3) and diacylglycerol (DAG) are formed. R1 and R2 are long-chain fatty acids in ester linkage with glycerol.

agonist molecule interacting with a single receptor may result in the formation of tens or hundreds of second messenger molecules, each of which might activate an enzyme that in turn catalyzes formation of hundreds of thousands of molecules of product. Most of the responses that are mediated by second messengers are achieved by regulating the activity of protein kinases that catalyze the phosphorylation of serine or threonine residues in effector proteins. Unlike responses that require synthesis of new cellular proteins, responses that result from these reactions occur very quickly; therefore, such second-messenger-mediated responses are turned on and off without appreciable latency. However, second messengers can also promote the phosphorylation of transcription factors and thus regulate expression of specific genes. These responses require considerably more time and are seen only after a delay.

Although a very large number of agonists act through surface receptors, to date only a few substances have been identified as second messengers. This is because receptors for many different extracellular signals utilize the same second messengers. When originally proposed, the hypothesis that the same second messenger might mediate the vastly different actions of many different agents was met with skepticism. The idea did not gain widespread acceptance until it was recognized that the special nature of a cellular response is determined by the particular enzymatic machinery with which a cell is endowed rather than by the signal that turns on that machinery. Thus, when activated, a hepatic cell makes glucose, and a smooth muscle cell contracts or relaxes.

The Cyclic AMP System

Cyclic AMP was the first of the second messengers to be recognized. The broad outlines of cAMP-mediated cellular responses to hormones are shown in Fig. 13. Cyclic AMP transmits a signal primarily by activating the enzyme protein kinase A (PKA). When cellular concentrations of cAMP are low, two catalytic subunits of PKA are firmly bound to a dimer of regulatory subunits which keeps them in an inactive state. An increase in cAMP leads to reversible binding of two molecules of cAMP to each regulatory subunit and liberates the catalytic subunits, which are now free to phosphorylate their substrates. Cyclic AMP that is not bound to regulatory subunits is degraded to 50-AMP by the enzyme cyclic AMP phosphodiesterase, which, though subject to regulation, is usually constitutively active. As cAMP concentrations fall, bound cAMP separates from the regulatory subunits, which then reassociate with the catalytic subunits, thus restoring the basal activity of PKA. Constitutively active phos-phatases rapidly remove phosphate groups from the

2. Control of Cell Function

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