Integration Of Simultaneous Signals

As must already be quite obvious, binding of a signal molecule to its receptor sets in motion intracellular signaling pathways that are both intricate and complex. Cells express receptors for multiple signaling molecules and are simultaneously bombarded with excitatory, inhibitory, or a conflicting mixture of excitatory and inhibitory inputs from different agents whose signaling pathways may run in parallel, intersect, coincide, diverge, and perhaps intersect again before influencing the final effector molecules. Some signaling pathways must compete for common substrates as well as for the final effector molecules that express the final alterations in cellular behavior. Target cells must integrate all inputs by summing them algebraically and sometimes geometrically and then respond accordingly. For example, in the hepatocyte, both glucagon and epinephrine stimulate adenylyl cyclase, each by way of its own G-protein-coupled receptor. The effects of these signals combine to produce a more intense activation of adenylyl cyclase than would result from either one alone. At the same time, these cells may also be receiving some input from insulin, an action of which is activation of cAMP phosphodiesterase, which breaks down cAMP. In the pancreatic beta cell, which secretes insulin, epinephrine binds to two classes of G-protein-coupled receptors: a2 receptors, which couple to adeny-lyl cyclase through a Gai, and fl receptors, which couple to adenylyl cyclase through a Gas. The two receptors thus transmit conflicting information; in this case, the inhibitory influence of the a2 receptor is stronger and prevails. Figure 21 shows an example of how several signaling pathways might operate simultaneously.

Integration occurs at various levels along signal transduction pathways, with cross-talk among the various G-protein-receptor-mediated signaling pathways or among the various tyrosine-phosphorylation-dependent pathways and among G-protein- and tyro-sine-kinase-mediated pathways and nuclear-receptor-mediated pathways. Integration thus is not limited to the rapidly expressed responses that result from phos-phorylation/dephosphorylation reactions but can also occur at the level of gene transcription or may involve a mixture of the two. In fact, phosphorylation of nuclear receptors catalyzed by MAP kinase, CAM kinase II, or PKC alters their ability to bind to other nuclear factors and hence may increase or decrease their ability to influence gene transcription. In responding simultaneously to multiple inputs, cells are able to preserve the signaling fidelity of individual hormones even when their transduction pathways appear to share common effector molecules. Understanding of how cells accomplish this is still incomplete, but part of the explanation may derive from the findings that many of the protein molecules involved in complex intracellular signal transmission do not float around freely in a cytoplasmic "soup" but are anchored at specific cellular loci by interactions with the cytoskeleton or membranes of intracellular organelles. Protein kinase A, for example, may be localized to specific regions in the cell by specialized proteins called AKAPs (A kinase anchoring proteins), and various forms of PKC are localized by

FIGURE 21 Cells may simultaneously receive inputs from agonists A, B, and C. Agonist B, acting through a G-protein-coupled receptor activates adenylyl cyclase (AC) through the a stimulatory subunit (as). Agonist C binds to its G-protein-coupled receptor which, through the inhibitory subunit (ai), inhibits adenylyl cyclase and, through the aq subunit, activates phospholipase C (PLC), resulting in the cleavage of phosphatidylinositol 4,5 bisphosphate (PIP2) and the release of diacylglycerol (DAG) and inositol trisphosphate (IP3). Agonist A, acting through a tyrosine kinase receptor, activates cAMP phosphodiesterase (PDE), which degrades cAMP. The cell must then sum all of these signals into an integrated response.

FIGURE 21 Cells may simultaneously receive inputs from agonists A, B, and C. Agonist B, acting through a G-protein-coupled receptor activates adenylyl cyclase (AC) through the a stimulatory subunit (as). Agonist C binds to its G-protein-coupled receptor which, through the inhibitory subunit (ai), inhibits adenylyl cyclase and, through the aq subunit, activates phospholipase C (PLC), resulting in the cleavage of phosphatidylinositol 4,5 bisphosphate (PIP2) and the release of diacylglycerol (DAG) and inositol trisphosphate (IP3). Agonist A, acting through a tyrosine kinase receptor, activates cAMP phosphodiesterase (PDE), which degrades cAMP. The cell must then sum all of these signals into an integrated response.

interacting with RACKs (receptors for activated C kinase). It is also possible that different agents use specific combinations of signal transduction pathways and that convergence of signals at critical reactions provides the reinforcement or dampening that enables cells to distinguish between agonists and appropriate cellular responses.

BIOSYNTHESIS, STORAGE, AND SECRETION OF CHEMICAL SIGNALS

Signal molecules generally are formed from simple precursors within the signaling cell, but occasionally common metabolites are used as signals without enzymatic modification. For example, glycine and glutamate are neurotransmitters in the brain. Sometimes only one or two enzymatic steps are needed to convert a common metabolite to a potent signal; histamine, for example, is formed by decarboxylation of the amino acid histidine, and adenosine is formed when adenosine monophosphate (50 AMP) is dephosphorylated. A complex series of enzymatic reactions may be used to build steroid hormones from a simple metabolite such as acetate, or secretory cells may accomplish the same end simply by putting the finishing touches on cholesterol that they take up from the blood (see Chapters 40 and 45-47). Enzymatic reactions may take place in the cytosol or within cellular organelles. Often, the biosynthetic pathway meanders from one cellular compartment to another, requiring energy-consuming, carrier-mediated transport to transfer precursors across intracellular membranes. As already described, all protein and peptide signal molecules, like other cellular proteins, are synthesized on ribosomes, processed in the endoplasmic reticulum and Golgi apparatus, and then packaged for later secretion by the process of exocytosis (Fig. 22). Specific reactions in biosynthesis and processing of signal molecules are discussed in subsequent chapters.

Secretory Granules and Vesicles

Cells usually maintain ample stores of the signal molecules they produce and therefore can respond rapidly and repeatedly to whatever changes in the internal or external environment might call forth secretion. Notable exceptions are the steroid hormones and the derivatives of arachidonic acid which are synthesized from stored precursors in the initial phase of the secretory process. Secretory products are usually segregated from the rest of the cell and stored in highly concentrated form in membrane-bound vesicles. In histological sections, stored secretory products appear as vesicular or granular inclusions for which the staining properties are often sufficiently distinctive to give the cell its name (e.g., eosinophils, chromaffin cells). At present, there is little reason to believe that synaptic vesicles that store neurotransmitters in nerve terminals are fundamentally different from the secretory granules of cells that secrete protein hormones or from the

Sacrelorv Vesicle

FIGURE 22 The leader sequence or signal peptide of proteins destined for secretion enters the cisternae of the endoplasmic reticulum even as peptide elongation continues. In the endoplasmic reticulum (1), the leader sequence is removed, (2) the protein is folded with the assistance of protein chaperons, sulfhydryl bridges may form (3), and carbohydrate may be added (glycosylation) (4). The partially processed protein is then entrapped in vesicles (5) that bud off the endoplasmic reticulum and fuse with the Golgi apparatus (6), where glycosylation is completed, and the protein is packaged for export in secretory vesicles (7) in which the final stages of processing take place.

Sacrelorv Vesicle

FIGURE 22 The leader sequence or signal peptide of proteins destined for secretion enters the cisternae of the endoplasmic reticulum even as peptide elongation continues. In the endoplasmic reticulum (1), the leader sequence is removed, (2) the protein is folded with the assistance of protein chaperons, sulfhydryl bridges may form (3), and carbohydrate may be added (glycosylation) (4). The partially processed protein is then entrapped in vesicles (5) that bud off the endoplasmic reticulum and fuse with the Golgi apparatus (6), where glycosylation is completed, and the protein is packaged for export in secretory vesicles (7) in which the final stages of processing take place.

granules in white blood cells that give rise to the name granulocyte.

Secretory vesicles are not inert receptacles; rather, they are active participants in the production, processing, and delivery of secretory products to the cell exterior. Their membranes are formed in the Golgi apparatus and are similar or identical in composition to the plasma membrane; they are selectively permeable and are endowed with the capacity for active transport of ions and complex molecules in either direction. Consequently, the composition of fluids in the interior of the vesicles is different from the composition of the cytosol. Carrier molecules in vesicular membranes account for the uptake of small signal molecules from the cytosol. Even the large amounts of signal molecules stored within vesicles have little osmotic impact because they are either complexed to macromolecules or precipitated out of solution.

The secretory granule provides a unique environment for enzymatic processing of secretory products and for protecting them from the degradative apparatus of the cell. Some enzymes required for synthesis or modification of secretory products may be intrinsic proteins in the vesicular membrane. In some cases, enzymes necessary for final processing of protein and peptide signal molecules are packaged along with the signal precursor before the vesicle is released from the Golgi apparatus. More than 200 different proteins have been found within the secretory vesicles that store the hormone insulin, but only a few of these are precursors of insulin or byproducts of processing of insulin.

Supplements For Diabetics

Supplements For Diabetics

All you need is a proper diet of fresh fruits and vegetables and get plenty of exercise and you'll be fine. Ever heard those words from your doctor? If that's all heshe recommends then you're missing out an important ingredient for health that he's not telling you. Fact is that you can adhere to the strictest diet, watch everything you eat and get the exercise of amarathon runner and still come down with diabetic complications. Diet, exercise and standard drug treatments simply aren't enough to help keep your diabetes under control.

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