Second Messengers

11 Key excerpts on "Second Messengers"

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  eBook - ePub

  Biochemistry of Signal Transduction and Regulation

  • Gerhard Krauss(Author)
  • 2014(Publication Date)
  • Wiley-VCH

    (Publisher)

  8 Intracellular Messenger Substances: “Second Messengers”

  Extracellular signals are registered by membrane receptors and conducted into the cell via cascades of coupled reactions. The first steps of signal transmission often take place in close association with the membrane, before the signal is conducted into the cell interior. The cell uses mainly two mechanisms for transmission of signals at the cytosolic side of the membrane and in the cell interior. First, signal transmission may be mediated by a protein–protein interaction, with the proteins involved being receptors, proteins with adapter function alone, or enzymes. Second, signals may be transmitted with the help of low-molecular-weight messenger substances, termed “Second Messengers.” The intracellular messenger substances are formed or released by specific enzyme reactions during the process of signal transduction and serve as effectors, by which the activity of proteins further along the sequence is regulated (Figure 8.1 ).

  Figure 8.1

  Function and formation of intracellular messenger substances in signaling pathways. Starting from the activated receptor, effector proteins next in sequence are activated that create an intracellular signal in the form of diffusible messenger substances. The hydrophilic messenger substances diffuse to target proteins in the cytosol and activate these for signal transmission further. Hydrophobic messenger substances, in contrast, remain in the cell membrane and diffuse at the level of the cell membrane to membrane-localized target proteins. PK, protein kinase; S, substrate of the protein kinase.

  8.1 General Properties of Intracellular Messenger Substances

  The intracellular messengers are diffusible signal molecules and reach their target proteins mostly by diffusion. Two types of intracellular messenger substance can be differentiated (Figure 8.1

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  Cell Signaling

  • Wendell A. Lim, Wendell Lim, Bruce Mayer, Tony Pawson(Authors)
  • 2014(Publication Date)
  • Garland Science

    (Publisher)

  6 Second Messengers: Small Signaling Mediators

  Much of the information transmitted within cells is carried by large macromolecules, such as proteins or nucleic acids. As we have seen in previous chapters, incoming signals can alter proteins in a number of ways—they can induce conformational changes, changes in complex formation, or post-translational modifications. However, information can also be carried by much smaller and simpler molecules; these include Ca2+ , various lipid-derived mediators, and the cyclic nucleotides cAMP and cGMP In this chapter, we discuss these small signaling mediators and their special properties.

  Properties Of Small Signaling Mediators

  When signaling inputs cause a change in the concentration of a small signaling mediator, that change is detected by downstream effector proteins that bind the mediator. Mediator binding leads to conformational changes in the effectors and ultimately to changes in their activity. Thus, information is conveyed by the concentration and distribution of these mediators, and how they change over time. These small signaling mediators are often referred to as Second Messengers, a term that derives largely from their historical discovery as signals that were produced downstream of hormone stimulation, where the hormone itself was considered the first messenger.

  Signaling by small-molecule mediators differs in several respects from more typical signaling mechanisms based only on changes in proteins. Changes in the concentration of the mediators can be quite rapid and can result in an enormous amplification of an input signal. And since most small signaling mediators are highly diffusible, their effects can spread rapidly throughout the cell.

  Small signaling mediators are controlled by an interplay of their production and elimination

  For a small signaling mediator to be an effective information-carrying molecule, its concentration must differ significantly under unstimulated and stimulated conditions. The steady-state concentration of these mediators is determined by a balance between the production of the mediator and its elimination. Usually, stimulation of the system by an input leads to an increase in the rate of synthesis of the mediator (for example, the allosteric activation of the enzyme that synthesizes the mediator), but stimulation can also involve a decrease in the breakdown or elimination of the mediator (Figure 6.1

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  Pharmacology

  Principles and Practice

  • Miles Hacker, William S. Messer, Kenneth A. Bachmann(Authors)
  • 2009(Publication Date)
  • Academic Press

    (Publisher)

  Chapter 6. Signal Transduction and Second Messengers

  Karen Lounsbury

  Outline

  6.1 Receptor Communication 103

  6.1.1 Ion Channels 103

  6.1.2 G-Protein Coupled Receptors 103

  6.1.3 Receptor Tyrosine Kinases 107

  6.1.4 Cytokine Receptors (Tyrosine Kinase-Associated Receptors) 109

  6.1.5 Intracellular Receptors 109

  6.1.6 Other Classes of Receptors 110

  6.2 Receptor/Second Messenger Crosstalk 110

  6.3 Signal Transduction Targets for Drug Discovery 111

  Central to the communication between cells is the process of signal transduction. Signal transduction is the mechanism by which cell surface receptors receive information from extracellular signals such as hormones and neurotransmitters, and amplify this information through the actions of Second Messengers. Second Messengers in turn activate pathways intrinsic to processes such as protein secretion, cell differentiation, and cell division. Many pharmacological agents elicit their clinical activity and side effects through interactions with receptors and/or their downstream signaling targets. As our understanding of receptor signaling has progressed, intracellular signaling molecules have become a major target of drug discovery. This chapter will review the major receptor-mediated signaling pathways and will outline current and future therapeutic strategies to target these pathways.

  6.1. Receptor Communication

  Receptors are the primary sensors of the cell environment, but ligand binding alone is useless without signal transduction. The effect of a pharmacologic agent on the ability of receptors to couple to downstream signals thus defines whether it will increase (agonist) or decrease (antagonist) the physiologic activity of the receptor. Selective regulation of the magnitude, time-course, and spread of the signal allows a single ligand to transmit a complex set of physiological effects. Signal transduction by receptors can be broken into four major categories:

  ▪ Ion channels ▪ G protein-coupled receptors ▪ Receptor tyrosine kinases ▪ Intracellular receptors

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  Cell Physiology Sourcebook

  A Molecular Approach

  • Nicholas Sperelakis(Author)
  • 2001(Publication Date)
  • Academic Press

    (Publisher)

  (1999). Sphingolipid metabolism in the regulation of bioactive molecules. Lipids 34, s5-sl 1. Martelli, A. M., Sang, N., Borgatti, P., Capitani, S., and Neri, L. M. (1999). Multiple biological responses activated by nuclear protein kinase C. /. Cell. Biochem. 74, 499-521. Missiaen, L., Parys, J. B., De Smedt, H., Sienaert, I., Bootman, M. D., and Casteels, R. (1996). Control of the Ca 2+ release induced by myo-inositol trisphosphate and the implication in signal transduc-tion. Subcell. Biochem. 26, 59-95. Spiegel, A. M. (ed.) (1998). G Proteins, Receptors, and Disease. Humana Press, Totowa New Jersey. Spiegel, S., Foster, D., and Kolesnick, R. (1996). Signal transduc-tion through lipid Second Messengers. Curr. Opin. Cell Biol. 8, 159-67. Streoli, M. (1996) Protein tyrosine phosphatases in signaling. Curr. Opin. Cell Biol. 8, 182-188. This page intentionally left blank John R. Dedman and Marcia A. Kaetzel 1 0 Calcium as an Intracellular Second Messenger: Mediation by Calcium-Binding Proteins I. Introduction Sidney Ringer provided the first report relating tissue and cellular function with Ca 2 + in 1883. He demonstrated that Ca 2 + was necessary for normal regular contractions of the isolated frog heart. Following this landmark study, Ca 2 + be-came an essential component of physiological saline solu-tions. There have been numerous studies relating Ca 2 + and cell functions including fertilization, development, differen-tiation, adhesion, growth, division, movement, contraction, and secretion. This evidence demonstrates a primary regula-tory role for ionized Ca 2 + in biological systems. Ca 2 + has also been associated with a number of diseases, particularly those of the muscular and nervous systems, in which this ion plays an important role in contraction and neurotransmitter release. Understanding the mechanism of Ca 2 + action has required approaches and expertise from distinct fields.

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  Biochemical Actions of Hormones V8

  • Gerald Litwack(Author)
  • 2012(Publication Date)
  • Academic Press

    (Publisher)

  In particular it seems that synarchic messengers are involved in coupling stimulus to response in most differentiated cells when these cells are ac-tivated to perform their specialized functions. The thesis can be most simply stated in the form of a schematic model (Fig. 18). In this model, extracellular messengers interacting with recep-tors on the cell surface lead to one or both of two changes either an in-crease in cAMP or of calcium ion in the cell cytosol. In those systems in which the concentration of both messengers rise in response to the same extracellular messenger, it is quite clear that there is a direct relationship between the two messenger systems at the very beginning of the stimulus-response coupling. This relationship becomes even more readily apparent when the subsequent intracellular events are analyzed. Each of the two messages interacts with one or more elements in the cell to control the others concentration, i.e., there is a dialogue be-tween the two. Each alters the sensitivity of response elements to the ef-fects of the other. Each regulates the same class of enzymes, protein kinases, and these in turn may regulate the activity of the same phospho-protein effectors to determine the ultimate cellular response. Plasticity is built into the system by the fact that each messenger controls the activity of one or more response element not influenced by the other. In those systems in which different extracellular messengers give rise to the two different intracellular messengers, cAMP and calcium, it is not immediately obvious that one is dealing with a universal system. How-ever, when one analyzes the intracellular interactions between the two messenger systems in such cells, the commonality and universality 1. The Messenger Function of Calcium in Endocrine Systems 99 1 RECOGNITION 2 TRANSDUCTION IcAMP | x @ © J C o ' + 1 4 RECEPTION I cAMP R I Ί CaCDR / < X ^ 7 TERMINATION 5 MODULATIOI 6 RESPONSE FIG.

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  Biology for AP® Courses

  • Julianne Zedalis, John Eggebrecht(Authors)
  • 2018(Publication Date)
  • Openstax

    (Publisher)

  Water-soluble hydrophilic ligands are unable to pass through the membrane; instead, they bind to cell-surface receptors, which transmit the signal to the inside of the cell. 9.2 Propagation of the Signal Ligand binding to the receptor allows for signal transduction through the cell. The chain of events that conveys the signal through the cell is called a signaling pathway or cascade. Signaling pathways are often very complex because of the interplay between different proteins. A major component of cell signaling cascades is the phosphorylation of molecules by enzymes known as kinases. Phosphorylation adds a phosphate group to serine, threonine, and tyrosine residues in a protein, changing their shapes, and activating or inactivating the protein. Small molecules like nucleotides can also be phosphorylated. Second Messengers are small, non-protein molecules that are used to transmit a signal within a cell. Some examples of Second Messengers are calcium ions (Ca 2+ ), cyclic AMP (cAMP), diacylglycerol (DAG), and inositol 394 Chapter 9 | Cell Communication This OpenStax book is available for free at http://cnx.org/content/col12078/1.6 triphosphate (IP 3 ). 9.3 Response to the Signal The initiation of a signaling pathway is a response to external stimuli. This response can take many different forms, including protein synthesis, a change in the cell’s metabolism, cell growth, or even cell death. Many pathways influence the cell by initiating gene expression, and the methods utilized are quite numerous. Some pathways activate enzymes that interact with DNA transcription factors. Others modify proteins and induce them to change their location in the cell. Depending on the status of the organism, cells can respond by storing energy as glycogen or fat, or making it available in the form of glucose. A signal transduction pathway allows muscle cells to respond to immediate requirements for energy in the form of glucose.

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  Identification of Neural Markers Accompanying Memory

  • Alfredo Meneses(Author)
  • 2013(Publication Date)
  • Elsevier

    (Publisher)

  Etienne-Manneville and Hall, 2002 ). The main function of small GTPases is to couple receptor activation to changes on cytoskeleton and gene transcription (see MAPK section).

  The Second Messengers

  Second Messengers refer to small intracellular molecules that are produced after the first messenger (hormone or neurotransmitter)-dependent receptor activation. Second Messengers are intended to activate intracellular signaling pathways that amplify the signal and culminate with the activation or inhibition of transcription factors, inducing a cellular response.

  The chemical nature of the second messenger is diverse: cyclic nucleotides, lipid derivatives and small active compounds, and some ions. The most studied Second Messengers are cyclic 3′5′-adenosine monophosphate (AMP) or cyclic guanosine monophosphate (GMP), calcium, DAG, IP3, and reactive oxygen and nitrogen species (ROS, NOS). In the following sections, we emphasize on the general characteristics and mechanisms of action of some of them.

  Cyclic Adenosine Monophosphate

  cAMP is a low-molecular-weight, hydrophilic second messenger formed by adenosine trisphosphate hydrolysis by the action of the enzyme adenylyl cyclase (AC) located at the plasma membrane and is activated by G-proteins.

  The class III AC is the most important member of the family. The structure of AC can be divided into five structural domains: the N-terminal cytoplasmic domain, the M1 and M2 domains formed by six transmembrane helixes each, and the C1 and C2 domains, which constitute the cytoplasmic catalytic site of the protein (Cooper, 2003 ). So far there have been described at least nine isoforms (type I to type IX) and are differentially regulated by both the α and βγ subunits of G-proteins, which can activate or inhibit its activity (Ishikawa and Homcy, 1997

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  Membranes and Cell Signaling

  • Edward Bittar(Author)
  • 1997(Publication Date)
  • Elsevier Science

    (Publisher)

  The subsequent intracellular biochemical events follow rather closely the blueprint described above in the case of blood platelets. Similar signal transduction pathways operate in the action of insulin, growth factors, and many other hormones (the major exception being hormones of the steroid family which interact directly with nuclear receptors). These signal transduction pathways have been conserved in eukaryotic evolution with even single-celled simple eukaryotes such as yeast cells, employ specific receptors and similar intracellular signaling pathways to effect modification of cell behavior (for example, in response to the secreted hormones, and the mating factors [Botstein and Fink, 1988; Herskowitz and Marsh, 1987]). Lipids as Second Messengers 495 This universality of signal transduction pathways has become the basis of a major revolution in molecular cell biology, since it has allowed the beginning of a molecular understanding of the mechanisms that operate in allowing cells to respond to stimuli from within and from their environment. Also, it has become clear that derangements of these regulatory signal transduction pathways result in important pathology. For example, many oncogenes (cancer-causing genes) are in fact abnormal forms of normal components of signal transduction and cell regula-tory pathways. Defects in signal transduction have also been associated with major autoimmune disorders and inflammatory conditions. Finally, understanding the structure and function of components of signal transduction pathways may result in targeted and rational drug development (for example, aspirin and non-steroidal antiinflanmiatory agents interfere with a key step in metabolism of the lipid second messenger arachidonic acid—see below). In this general context, many lipids are emerging as key components of these signal transduction pathways.

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  Lecture Notes

  Human Physiology

  • Ole H. Petersen(Author)
  • 2019(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  The opening and closing of the gap junctional channels may be regulated by changes in voltage, cytosolic pH and intracellular messengers in much the same way that membrane ion channels are regulated (see below). For example, an increase in the intracellular cyclic adenosine monophosphate (cAMP) concentration can rapidly increase the permeability of gap junctions in certain tissues, whereas an increase in intracellular acidity can close the channels. This in turn will influence the rate of transfer of messengers between adjacent cells.

  2.2 How cells respond to external stimuli

  Cells respond to a variety of external stimuli and transduce these signals into electrical and biochemical changes. In many instances this involves the interaction of a signal with a receptor in the plasma membrane. This may lead directly to activation of ion channels, but more commonly it induces the production of intracellular messengers that then regulate cell function. Guanosine triphosphate (GTP) regulatory proteins play a crucial role in coupling receptor occupancy to the generation of an intracellular biochemical cascade. Recognized intracellular pathways include the cAMP, the cyclic guanosine monophosphate (cGMP) and phosphoinositide systems. Ca2+ is a particularly important intracellular regulator; its cytosolic activity may be raised by influx across the plasma membrane or by release from intracellular stores controlled by the phosphoinositide system.

  In some cases there is a direct link between a stimulus and activation of ion channels. Examples include stretch-activated channels in touch receptors and voltage-sensitive channels in excitable tissues (see Chapter 4 ). However, for chemical stimuli (e.g. gustatory, olfactory, neurotransmitters, hormones, growth factors, etc.) the first event leading to a cellular response is the interaction of the chemical signal (ligand) with its receptor.

  Receptors

  Receptors are molecular entities, either proteins or glycoproteins, which bind ligands with high affinity. (Note that cells, or components of cells, that respond to sensory stimuli are also referred to as ‘receptors’ but the two should not be confused.) Receptors for ligands that do not penetrate cells readily (e.g. most neurotransmitters, peptide hormones, etc.) are located in the plasma membrane, but some lipophilic ligands (e.g. steroid and thyroid hormones) have their receptors in the cytoplasm or nucleus.

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  Karp's Cell and Molecular Biology

  • Gerald Karp, Janet Iwasa, Wallace Marshall(Authors)
  • 2021(Publication Date)
  • Wiley

    (Publisher)

  If the particulate fraction of a liver homogenate was isolated and incubated with the hormone, some substance was released; when added to the supernatant 700 CHAPTER 15 Cell Signaling and Signal Transduction: Communication between Cells fraction, this substance activated the soluble glycogen phos- phorylase molecules. Sutherland identified the substance released by the membranes of the particulate fraction as cyclic adenosine monophosphate (cyclic AMP, or simply cAMP). This discovery is heralded as the beginning of the study of signal transduction. As will be discussed shortly, cAMP stimulates glucose mobilization by activating a protein kinase that adds a phosphate group onto a specific serine residue of the glycogen phosphorylase polypeptide. Phosphatidylinositol-Derived Second Messen- gers Not very long ago, the phospholipids of cell mem- branes were considered to be strictly structural molecules that made membranes cohesive and impermeable to aqueous sol- utes. Our appreciation of phospholipids has increased with the realization that these molecules form the precursors of a num- ber of Second Messengers. Phospholipids of cell membranes are converted into Second Messengers by a variety of enzymes that are regulated in response to extracellular signals. These enzymes include phospholipases (lipid-splitting enzymes), phospholipid kinases (lipid-phosphorylating enzymes), and phospholipid phosphatases (lipid-dephosphorylating enzymes). Phospholipases are enzymes that hydrolyze spe- cific ester bonds connecting the different building blocks of a phospholipid molecule. Figure 15.9 shows the cleavage sites within a generalized phospholipid that are attacked by the main classes of phospholipases. All four of the enzyme classes can be activated in response to extracellular signals, and their products function as Second Messengers.

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  Karp's Cell Biology

  • Gerald Karp, Janet Iwasa, Wallace Marshall(Authors)
  • 2018(Publication Date)
  • Wiley

    (Publisher)

  As researchers analyze the massive amount of data obtained from sequencing Arabidopsis and other plant genomes, the similarities and differences between plant and animal signaling pathways should become more apparent. 15.12 The Role of Calcium as an Intracellular Messenger Calcium ions play a significant role in a remarkable variety of cellular activities, including muscle contraction, immune responses, cell division, secretion, fertilization, synaptic transmission, metabolism, transcription, cell movement, and cell death. In each of these cases, an extracellular message is received at the cell surface and leads to a dramatic increase in concentra- tion of calcium ions within the cytosol. The concentration of cal- cium ions in a particular cellular compartment is controlled by the regulated activity of Ca 2+ pumps, Ca 2+ exchangers, and/or Ca 2+ ion channels located within the membranes that surround the compartment (as in Figure 15.28). The concentration of Ca 2+ ions in the cytosol of a resting cell is maintained at very low levels, typically about 10 7 M. In contrast, the concentration of this ion in the extracellular space or within the lumen of the ER or a plant cell vacuole is typically 10,000 times higher than the cytosol. The cytosolic calcium level is kept very low because (1) Ca 2+ ion channels in both the plasma and ER membranes are normally kept closed, making these membranes highly impermeable to this ion, and (2) energy‐driven Ca 2+ transport systems of the plasma and ER membranes pump calcium out of the cytosol. 2 Abnormal elevation of cytosolic Ca 2+ concentration, as can occur in brain cells following a stroke, can lead to massive cell death. IP 3 and Voltage‐Gated Ca 2+ Channels We have described in previous pages two major types of signal- ing receptors, GPCRs and RTKs.

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