Biological Sciences
Cyclic AMP
Cyclic AMP (cAMP) is a signaling molecule that plays a crucial role in various cellular processes. It is formed from ATP and acts as a second messenger, transmitting signals from hormones and neurotransmitters to regulate processes such as metabolism, gene expression, and cell growth. cAMP exerts its effects by activating protein kinase A and other downstream signaling pathways.
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11 Key excerpts on "Cyclic AMP"
eBook - ePub- Enrique Pimentel(Author)
- 2017(Publication Date)
- CRC Press(Publisher)
Chapter 4Cyclic Nucleotides
I. Introduction
Cyclic nucleotides are purine derivative compounds that have a key role as second messengers in the mechanism of action of externally signaling agents including hormones, growth factors, regulatory peptides, and neurotransmitters. Two cyclic nucleotides, cyclic adenosine 3’,5’-monophosphate (Cyclic AMP or cAMP) and cyclic guanine 3’5’-monophosphate (cyclic GMP or cGMP), are involved in such functions, but the first of them, cAMP, is considered to be the most important cyclic nucleotide second messenger in mammalian cells.1 -6The possible role of a third cyclic nucleotide, cyclic cytidine 3’,5’-monophosphate (cCMP), in the regulation of cellular functions by external stimuli is controversial.7II. Cyclic AMP and the Adenylyl Cyclase System
cAMP was discovered during a study on the effects of glycogenolytic hormones (glucagon and epinephrine) in liver slices and homogenates, which were associated with the accumulation of a heat-stable, dialyzable adenosine nucleotide.8 This molecule, in the presence of ATP, Mg2+ , and a cytoplasmic enzyme, was able to convert liver phosphorylase from an inactive precursor to an active form.9 The active substance, identified as cAMP, was shown to be biosynthesized from ATP by the action of a specific enzyme, adenylyl cyclase, which is an integral component of the plasma membrane.10 Methyl xanthines such as caffeine, aminophylline, and theophylline, can prevent the conversion of cAMP to an inactive noncyclic metabolite, 5’ adenosine monophosphate (5’ AMP), which is catalyzed by cAMP phosphodiesterase.11 Thus, by prolonging the survival of cAMP, methyl xanthines produce physiological effects that resemble those of many hormones that activate adenylyl cyclase. It was further demonstrated that the activation of glycogen phosphorylase by cAMP depends on the stimulation of a protein kinase, the cAMP-dependent protein kinase (protein kinase A), which transfers the terminal phosphate of ATP to specific serine and/or threonine residues in the enzyme undergoing activation.12
- Gerhard Krauss(Author)
- 2014(Publication Date)
- Wiley-VCH(Publisher)
- Intracellular messenger substances can be formed and degraded again in specific enzyme reactions. Via enzymatic pathways, large amounts of messenger substances can be repeatedly and rapidly created and inactivated.
- Messenger substances, such as Ca2+ , may be stored in special storage organelles, from which they can be rapidly released by a signal.
- Messenger substances may be produced in a location-specific manner, and they may also be removed or inactivated according to their location. It is therefore possible for the cell to create signals that are spatially and temporally limited.
8.2 Cyclic AMP
Summary
The second messenger 3′,5′-Cyclic AMP (cAMP) is produced from ATP by the action of adenylyl cyclases, and is degraded by the action of phosphodiesterases. The signaling function of cAMP is based primarily on binding to protein kinase A (PKA), ion channels, and the transcription factor Epac. To a large part, signaling by cAMP is restricted to discrete locations at the cell membrane and intracellular membrane compartments where cAMP production, binding to its target proteins and cAMP degradation each occur within defined supramolecular complexes organized by specific anchoring proteins such as the A-kinase anchoring proteins (AKAPs).3′,5′-Cyclic AMP (cAMP), which is produced from ATP by the action of adenylyl cyclases (ACs; see Section 7.7.1 and Figure 7.30), influences many cellular functions including gluconeogenesis, glycolysis, lipogenesis, muscle contraction, membrane secretion, learning processes, ion transport, differentiation, growth control, and apoptosis.The concentration of cAMP is controlled primarily by two means, namely via new synthesis by ACs and via degradation by phosphodiesterases. Both enzymatic activities cooperate in forming cAMP gradients in the cell with specific temporal and local characteristics. An important feature of cAMP signaling is the colocalization of the enzymes of cAMP metabolism and the targets of cAMP. For example, ACs, phosphodiesterases and protein kinase A have been found to colocalize at the same subcellular sites, allowing for a precise control of cAMP formation, degradation, and target selectivity.
Available until 15 Nov |Learn moreTherapeutic Targets
Modulation, Inhibition, and Activation
- Luis M. Botana, Mabel Loza(Authors)
- 2012(Publication Date)
- Wiley(Publisher)
Chapter 1 cAMP-Specific Phosphodiesterases: Modulation, Inhibition, and Activation R. T. Cameron and George S. Baillie Molecular Pharmacology Group, Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, Wolfson Building, University of Glasgow, Glasgow, UK 1.1 Introduction Cell surface, 7-span, transmembrane receptors recognize various environmental stimuli and transform them into intracellular signals via associated G proteins. This allows cells, tissues, and organs to alter specific aspects of their homeostasis in response to physical or chemical challenges. As such, cellular signals propagated in this way must be highly regulated so that their amplitude and timing produce a measured, appropriate response. The signal must be strong enough to produce the desired effect but also be transient so that the cell can easily prepare for other potential challenges. Additionally, the signal must also be targeted to the correct functional machinery, which often resides in discrete intracellular locations; hence signaling must be compartmentalized. To achieve all of these goals, cells have developed signaling molecules known as second messengers to convey complex information from receptors, temporally and in three dimensions, into the cell to signaling nodes where functional decisions are made. Although it is known that second messengers can take the form of lipids, gasses, ions, or nucleotides, discoveries around one such messenger, cyclic adenosine monophosphate (cAMP), provided the conceptual framework on which the second messenger concept was based [1]. Soon after its discovery in 1958 [2], it was realised that cAMP was synthesized at the membrane by adenylate cyclase in response to hormones and degraded to 5′-AMP by the action of cyclic nucleotide phosphodiesterases in the cytoplasm (reviewed in Ref. 1)
eBook - PDF- G Robison(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
CHAPTER 2 Cyclic AMP and Hormone Action I. Introduction ^ II. Hormones ^ III. Receptors and Second Messengers 22 IV. The Intracellular Level of Cyclic AMP 29 A. Normal Levels 29 B. Effects of Hormones 30 C. Effects of Drugs 32 D. Effects of Ions 33 E. Third Messengers 34 V. Experimental Approaches Used in the Study of Hormones which Stimulate Adenyl Cyclase 36 A. Studies with Broken Cell Preparations 37 B. Studies with Intact Tissues 38 C. Phosphodiesterase Inhibitors * 4 1 D. Exogenous Cyclic AMP 4 E. Hormones which May or May Not Affect Adenyl Cyclase 4 5 VI. Two Major Problems 6 VII. Addendum 6 I. INTRODUCTION Cyclic AMP is now recognized as a versatile regulatory agent which acts to control the rate of a number of cellular processes. It occurs in all 17 18 2. Cyclic AMP AND HORMONE ACTION animal species investigated, including bacteria and other unicellular organisms, although it has so far not been detected in higher plants. In those cells in which it occurs, Cyclic AMP seems to play primarily a regulatory rOle, and thus differs from many biochemical agents which may at times play a regulatory role but which have other functions be-sides. Cyclic AMP does not seem to be essential, for example, in the same sense that ATP and the calcium ion are essential. Many basic cel-lular processes come to a complete halt in the absence of one or the other of these agents, whereas Cyclic AMP seems to act in most cases to either increase or decrease the rates of cellular processes which would occur at one rate or another even in its complete absence. Even this generalization may be invalid, however. Information about Cyclic AMP is accumulating at such a rapid rate that we are probably not in a very good position to generalize about it at all. It seems possible, for example, that if some cells which normally contain Cyclic AMP were completely depleted of it, they might well be incapable of anything ap-proaching normal function.
eBook - PDF- C.B. Anfinsen(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
1. Number of publications dealing with Cyclic AMP 1958-1970 (Sept.); survey based on approx-imately 70 journals (19). From Jost and Rick-enberg, Ann. Rev. Biochem., 1971. called the second messenger hypothesis. The ^ix^t messenger is a polypeptide hormone, or some other hor-mone circulating in the plasma, which finds its target site on the surface of a cell. I have drawn the inner membrane at some distance from the surface because the overall membrane must be very thick to accommodate all the people working on it. The hormone binds to the cell, which implies that there is a receptor site on the outside, and in some way stimulates the formation of Cyclic AMP from ATP at the other side of the cell membrane, some distance away. The specificity is built into the receptor. Presumably some receptor subunit recognizes the hormone. 66 CURRENT TOPICS IN BIOCHEMISTRY Inside cell ATP Hormone H Receptor site Catalytic site Cyclic AMP GTP. Outer membrane Inner membrane Fig, 2, A general model. Different hormones activating adenylate cyclase in dif-ferent tissues must interact with different receptors. After Cyclic AMP has been formed it can be broken down to 5 f -AMP by a phosphodiesterase (as I will dis-cuss below, there are now many such phosphodiesterases) or it can instruct the tissue to do the thing that it is already programmed to do. If associated with a thy-roid cell, Cyclic AMP tells it to make and secrete thyroid hormone. If fat tissue is the receptor, the instruction may induce the breakdown of triglyceride and fatty acids, and so forth. Figure 3 shows two possible space-filling models of Cyclic AMP. The molecule can be in either anti or syn position, with the ribose either extended away from or bent back underneath the purine ring. No one really knows in what configuration Cyclic AMP is active. Table 1 summarizes some of the actions of Cyclic AMP (31).
eBook - PDF- Franklyn Bolander(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
PART Transduction 129 This page intentionally left blank CHAPTER 7 Cyclic Nucleotides CHAPTER OUTLINE I. Introduction II. Criteria III. History IV. Cyclic AMP Pathway V. Cyclic GMP Pathway VI. Phosphodiesterases VII. Cyclic CMP Pathway VIII. Protein Kinases IX. Transcellular Activation of Protein Kinase A X. Summary References 131 132 7. Cyclic Nucleotides /. Introduction Because peptide and certain other hormones cannot cross the plasma mem-brane, they must interact with their receptors on the cell surface. Therefore, if the hormone is to have an effect on cellular processes, a signal must be gener-ated from the other side of the membrane; this signal can then carry out the actions of the hormone. If the hormone itself is considered to be the primary, or first, messenger, then the signal becomes the second messenger. This part discusses all of the major second messengers. Chapter 7 begins with a brief discussion of the criteria for these mediators and then presents the cyclic nucleotides. Chapter 8 describes the role of phospholipids in signal transduction: phosphatidylinositol is involved with the elevation of intracellu-lar calcium and the activation of a protein kinase, whereas phosphatidylcho-line may affect membrane fluidity and generate the precursor for the eicosan-oids. Chapter 9 describes a number of mediators that are not as well defined as the cyclic nucleotides and calcium; they include the polyamines, oligosaccha-rides, and the cytoskeleton. Chapter 10 is a general synthesis of the preceding three chapters and describes how these second messengers can directly affect cellular processes. //. Criteria How does one identify a second messenger for a hormone; that is, what characteristics should a molecule have in order to be called a second messen-ger? Basically, there are five criteria that a compound must satisfy and they will be discussed using glycogen breakdown as an example: in the liver, glucagon stimulates glycogenolysis via cAMP.
eBook - PDFMedicinal Chemistry—III
Main Lectures Presented at the Third International Symposium on Medicinal Chemistry
- P. Pratesi(Author)
- 2013(Publication Date)
- Butterworth-Heinemann(Publisher)
depend. None 8.6 30.1 9.6 13.4 12.2 Cyclic AMP 135.4 142.2 38.1 45.6 34.1 Cyclic G M P 85.9 124.3 31.8 39.8 43.7 Cyclic TuMP 131.4 141.2 38.5 43.9 42.5 5'-Methylene analogue of Cyclic AMP 27.9 142.3 17.1 35.2 13.3 3'-Methylene analogue of Cyclic AMP 9.0 35.1 8.7 11.7 11.7 421 M. NELBOECK, G. MICHAL, G. WEIMANN, R. PAOLETTI A N D F. BERTI K T 8 ΙΟ 7 10 6 cAMP 1 1 1 8 -SCH3 2.4 1.10 0.94 8 -Br 0.73 0.65 0.93 8-N(CH 3 ) 2 0.43 0.56 0.91 8 -N H C H 2 C 6 H 5 0 0.091 0.56 8 -NHCH 2 CH 2 OH 0 0 0 * A c t i v i t y m e a s u r e d as p m o l e s o f 3 2 P i n c o r p o r a t e d i n t o h i s t o n e . The different behaviour of cAMP analogues towards protein kinase from different tissues is the molecular basis for the effects in more complicated metabolic processes. In the following chapters, a brief discussion of the current knowledge of cAMP-function in the different systems, the effect of analogues on enzymes in cell-free systems, on isolated tissues and finally in vivo is presented. For simplification, statistical data shown in the original papers have been omitted. GLYCOGENOLYSIS The molecular mechanisms, by which the cAMP stimulates the trans-formation of liver and muscle glycogen into glucose are well known due to the work of Sutherland, Krebs and of Greengard (Figure 9). A cAMP-dependent protein kinase activates by phosphorylation another kinase (Phosphorylase kinase), which, in turn, converts the inactive phosphorylase-b into the active Phosphorylase-a by phosphorylation with ATP. Simul-taneously, the glycogen synthetase is inhibited by phosphorylation with the same protein kinase which initiates the glycogenolysis. The biological significance of this enzyme cascade lies in the extreme amplification of the hormonal input signal. The concentration of hormones in the blood stream is very small (about 10~ X 1 M for peptide hormones, and somewhat higher for catecholamines). This signal of the first messenger is already amplified by 422 itself.
eBook - PDF- Gerald Litwack(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
In order to progress in our understanding of the role of Cyclic AMP in the nervous system, it will be necessary to clarify and/or resolve a number of specific issues, some of which in themselves may turn out to be much more complex than we might conceive them to be at present. These include the problem of identifying various adenylate cyclase systems as associated with glial, vascular, or specific neuronal cell types. Also, there is the problem of differences in responsiveness of intact tissue and homogenate preparations with respect to influence of transmitters of Cyclic AMP formation, and also that of relating either of these back to the in vivo situation. We need to know much more about multireceptor interactions at the cell surface and the interrela-tionships of Cyclic AMP, cyclic GMP, and possibly other second mes-sengers within the cell. The role of GTP and Ca 2+ in modulation of adenylate cyclase and other related processes must also be further in-vestigated. The existence and relevance of adenosine receptors must be resolved in order to be able to put into perspective a great deal of information already accumulated concerning influences of biogenic 9. Cyclic AMP and Transmitter Function 477 amines on Cyclic AMP formation. This in itself may be part of the larger question of multireceptor interactions. Many of these questions would be greatly helped by achieving the ability to reassemble an in-tact synaptic membrane from its component parts. Such an accom-plishment would also help in attaining an understanding of the de-tailed mechanisms by which Cyclic AMP might alter membrane prop-erties and thereby modulate synaptic events. Another exciting area for exploration involves evaluation of the role of cyclic nucleotide systems as well as changes in cyclic nucleotide systems themselves in development and aging of the nervous system.
eBook - ePub- Linda J. Van Eldik, D. Martin Watterson(Authors)
- 2012(Publication Date)
- Academic Press(Publisher)
Since its discovery (1) as a subunit and activator of cyclic nucleotide phosphodiesterase (PDE), the calcium signal transducer, calmodulin (CaM), has been known to mediate the interaction of signal transduction pathways involving the elevation of intracellular calcium with cyclic nucleotide signaling. It is now becoming more evident that not only does CaM regulate the degradation of cyclic nucleotides by activating CaM-stimulated PDEs, but it also modulates in both positive and negative ways the synthesis of cAMP and cGMP via inhibition or activation of adenylyl cyclase (AC) or activation of guanylyl cyclase via a CaM-sensitive nitric oxide synthase (2, 3). This chapter focuses on the role that CaM plays in regulating (a) adenylyl cyclase (adenylate cyclases) and (b) cyclic nucleotide phosphodiesterases, the identity and manner by which CaM regulates these different isozymes, the mechanisms by which CaM elicits its regulatory function, the distribution of these enzymes in the different cell types and organs of mammals, and the physiological contexts in which these enzymes are important for the “normal” signal transduction and functioning of cells, organs, and systems.II. CALMODULIN-REGULATED ADENYLYL CYCLASES
The adenylyl cyclases catalyze the formation of cAMP, an important intracellular message in almost all animal cells. They are regulated by stimulatory and inhibitory receptors coupled to their catalytic subunits through stimulatory (Gs ) and inhibitory (Gi ) GTP-binding, regulatory proteins. Intracellular Ca2+ also modulates adenylyl cyclase activity in several tissues, and the Ca2+ -sensitive adenylyl cyclases provide mechanisms for “cross-talk” between Ca2+ and cAMP signal transduction systems. In some cases, adenylyl cyclases function as signal integrators and respond synergistically to multiple extracellular and intracellular signals.Characterization of adenylyl cyclases was advanced greatly by purification of the enzymes and isolation of cDNA clones encoding mammalian adenylyl cyclases. There are at least nine distinct adenylyl cyclases, each having its own unique regulatory properties. Although adenylyl cyclases are regulated by multiple effector molecules, including Ca2+
- George Rothblat(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
Thus the adenylate cyclase system would be mainly responsive to those hormones or factors concerned with the synthesis and release of specialized product. A loss of any one of the several steps linking hormonal stimulation to expression of differentiated function when cells are transfered from in vivo to tissue culture in vitro, could thus result in loss of that differentiated function. Also to be considered in relationship to the actions of cyclic nucleotides is the process of cell transformation. Well regulated normal cells are sensitive to inhibition by at least three different environmental signals: contact with other cells (Abercrombie, 1970; Todaro and Green, 1963; Stoker and Rubin, 1967), deprivation of serum (Todaro et al, 1967; Holley and Kiernan, 1968; Stoker and Piggott, 1974), and absence of an appropriate surface for growth (Macpherson 8. Cyclic Nucleotides 335 and Montagnier, 1964). Cells transformed by virus or chemical agents may lose sensitivity to all three signals and thus grow despite cell-to-cell contact, reaching a very high density and forming multilayers of cells (Todaro and Green, 1964). Furthermore, they may grow even when serum is reduced manyfold (Vogel and Pollack, 1973), form spherical colonies when suspended in methyl cellulose gel (Stoker et al, 1968; Vogel et al, 1973), or grow well in suspended culture (Abercrombie and Ambrose, 1962). It thus appears that the most common change in transformed cells is the loss of normal growth control mechanisms (Hershko et al, 1971; Kram et al, 1973;Holley, 1975). Numerous studies of the adenylate cyclase system in neoplastic cells indicated that an apparent defect in some component of Cyclic AMP metabolism exists in most neoplastic cells examined (Chlapowski et al, 1975; Pastan et al, 1975).
eBook - PDF- Gerald Litwack(Author)
- 2012(Publication Date)
- Academic Press(Publisher)
B., and Hanson, R. W. (1977). /. Biol. Chem. 252, 655-662. 2. Molecular Aspects of Cyclic AMP Action 63 Jastorff, B., Hoppe, J., and Morr, M. (1979). Eur. J. Biochem. 101, 555-561. Johnson, E. M. (1977). Adv. Cyclic Nucleotide Res. 8, 267-309. Johnson, G. L., Bourne, H. R., Gleason, M. K., Coffîno, P., Insel, P. A., and Melmon, K. L. (1979). Mol. Pharmacol. 15, 16-27. Jost, J.-P., and Averner, M. (1975). /. Theoret. Biol. 49, 337-344. Jungmann, R. A., and Russell, D. H. (1977). Life Sei. 20, 1787-1798. Keely, S. L., Corbin, J. D., and Park, C. R. (1975). Proc. Natl. Acad. Sei. U.S.A. 72, 1501-1504. Kellems, R. E., Morhenn, V. B., Pfendt, E. A., Ait, F. W., and Schimke, R. T. (1979)./. Biol. Chem. 254, 309-318. Kerlavage, A. R., and Taylor, S. S. (1980). /. Biol. Chem. 255, 8483-8488. Kerlavage, A. R., and Taylor, S. S. (1982). /. Biol. Chem. 257, 1749-1754. Knight, B. L., and Skala, J. P. (1977). /. Biol. Chem. 252, 5356-5362. Krebs, E. G. (1972). Curr. Top. Cell. Regul. 5, 99-133. Krebs, E. G., and Beavo, J. A. (1979). Annu. Rev. Biochem. 48, 923-959. Kudlow, J. E., Rae, P. A., Gutmann, N. S., Schimmer, B. P., and Burrow, G. N. (1980). Proc. Natl. Acad. Sei. U.S.A. 77, 2767-2771. Kudlow, J. E., Watson, R. K., and Gill, G. N. (1981). /. Cyclic Nucleotide Res. 7, 151-159. Kuo, J. F., and Greengard, P. (1969). Proc. Natl. Acad. Sei. U.S.A. 64, 1349-1355. Lai, E., Rosen, O. M., and Rubin, C. S. (1982). /. Biol. Chem. 257, 6691-6696. Lamers, W. H., Hanson, R. W., and Meisner, H. M. (1982). Proc. Natl. Acad. Sei. U.S.A. 79, 5137-5141. Langan, T. A. (1973). Adv. Cyclic Nucleotide Res. 3, 99-153. Lee, P. D., Radloff, D., Schweppe, J. S., and Jungmann, R. A. (1976). /. Biol. Chem. 251, 914-921. Lemaire, I., and Coffîno, P. (1977a). /. Cell. Physiol. 92, 437-446. Lemaire, I., and Coffîno, P. (1977b). Cell 11, 149-155. Liu, A. Y.-C. (1982). /. Biol. Chem. 257, 298-306. Liu, A. Y.-C, Chan, T., and Chen, K. Y. (1981). Cancer Res. 41, 4579-4587.
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