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Lodish H, Berk A, Zipursky SL, et al. Molecular cabinet Biology. Fourth edition. Brand-new York: W. H. Freeman; 2000.

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Communication by extracellular signal usually involves six steps: (1) synthetic and(2) relax of the signaling molecule by the signaling cell; (3) transfer of thesignal come the target cell; (4) detection of the signal through a certain receptorprotein; (5) a change in moving metabolism, function, or development triggered bythe receptor-signal complex; and (6) removed of the signal, which often terminatesthe to move response.

In countless eukaryotic microbe (e.g., yeast, slime molds, and protozoans),secreted molecule coordinate the aggregation that free-living cell for sex-related matingor differentiation under particular environmental conditions. Chemicals released by oneorganism the can change the behavior or gene expression of other organisms of thesame species are referred to as pheromones.Yeast mating-type factors discussed later in this chapter room a well-understoodexample the pheromonemediated cell-to-cell signaling. Part algae and animals alsorelease pheromones, commonly dispersing them into the waiting or water, come attractmembers of opposing sex. An ext important in plants and animals room extracellularsignaling molecules that function within an biology to controlmetabolic processes within cells, the growth of tissues, the synthesis and secretionof proteins, and the ingredient of intracellular and also extracellular fluids. Thischapter focuses on such cell-to-cell signaling in single-celled eukaryotes and also in avariety of higher eukaryotes, specifically mammals.

Signaling Molecules operate over Various distances in Animals

In animals, signaling by extracellular, secreted molecules deserve to be share intothree types — endocrine, paracrine, orautocrine — based ~ above the distance over i beg your pardon thesignal acts. In addition, specific membrane-bound protein on one cabinet candirectly signal an adjacent cell (Figure20-1).


Figure 20-1

General schemes that intercellular signaling in animals. (a – c) Cell-to-cell signaling byextracellular chemicals wake up over distances from a few micrometersin autocrine and paracrine signaling to number of meters in endocrinesignaling. (more...)

In endocrine signaling, signaling molecules, referred to as hormones, plot on target cell distantfrom their website of synthetic by cell of endocrine organs. In animals, anendocrine hormone usually is carried by the blood indigenous its site of release toits target.

In paracrine signaling, the signaling molecules exit by a cellonly affect target cells in nearby proximity come it. The conduction of one electricimpulse from one nerve cell to another or from a nerve cabinet to a muscle cell(inducing or inhibiting muscle contraction) wake up via paracrine signaling. Therole the this form of signaling, mediated through neurotransmitters, in transmitting nerve impulses isdiscussed in chapter 21. Manysignaling molecules regulating breakthrough in multicellular organisms also actat quick range. Some of these molecule are disputed in thing 23.

In autocrine signaling, cells respond to substancesthat they themselves release. Plenty of growthfactors action in this fashion, and cultured cells regularly secrete growthfactors the stimulate their own growth and also proliferation. This type ofsignaling is specifically common in tumor cells, countless of which overproduce andrelease growth determinants that wake up inappropriate, unregulated proliferationof themselves also as adjacent nontumor cells; this procedure may lead toformation the tumor mass.

Some compounds have the right to act in 2 or even three varieties of cell-to-cell signaling.Certain small amino mountain derivatives, such as epinephrine, role both together neurotransmitters(paracrine signaling) and as systemic hormone (endocrine signaling). Someprotein hormones, such as epidermal expansion factor (EGF), room synthesized as theexoplasmic component of a plasma- membrane protein; membrane-bound EGF deserve to bind toand signal an surrounding cell by direct contact. Cleavage through a protease releasessecreted EGF, i m sorry acts as an endocrine signal on distant cells.

Receptor proteins Exhibit Ligand-Binding and also Effector Specificity

As noted earlier, the cellular response to a details extracellular signaling molecule counts on the binding come a specific receptor protein situated on thesurface of a target cell or in its cell nucleus or cytosol. The signaling molecule (ahormone, pheromone, or neurotransmitter) acts as a ligand, which binding to, or “fits,” asite ~ above the receptor. Binding of a ligand come its receptor reasons aconformational change in the receptor the initiates a sequence of reactionsleading to a certain cellular response.

The response of a cell or organization to details hormones is dictated by theparticular hormone receptors it possesses and also by the intracellular reactionsinitiated through the binding of any one hormone come its receptor. Different celltypes might have various sets that receptors because that the very same ligand, each of whichinduces a different response. Or the very same receptor may take place on assorted celltypes, and binding that the exact same ligand may cause a different solution in eachtype that cell. Clearly, different cells respond in a range of ways to the sameligand. For instance, acetylcholine receptor are found on the surface ar ofstriated muscle cells, heart muscle cells, and also pancreatic acinar cells. Releaseof acetylcholine indigenous a neuron adjacent to a striated muscle cabinet triggerscontraction, conversely, release nearby to a heart muscle slows the rate ofcontraction. Release adjacent to a pancreatic acinar cell triggers exocytosis ofsecretory granules that contain digestive enzymes. Top top the various other hand, differentreceptor-ligand complexes can induce the exact same cellular response in some celltypes. In liver cells, for example, the binding of one of two people glucagon to itsreceptors or of epinephrine come its receptors deserve to induce deterioration of glycogenand relax of glucose right into the blood.

These examples show that a receptor protein is identified by bindingspecificity because that a particular ligand, and the resultinghormone-ligand facility exhibits effector specificity (i.e.,mediates a particular cellular response). For instance, activation the eitherepinephrine or glucagon receptor on liver cell by binding of their respectiveligands induces synthetic of cyclic AMP (cAMP), one of severalintracellular signaling molecules, termed second messengers, i beg your pardon regulate assorted metabolic functions; as aresult, the impacts of both receptor on liver-cell metabolism space the same.Thus, the binding specificity the epinephrine and also glucagon receptor differ, buttheir effector specificity is identical.

In many receptor-ligand systems, the ligand shows up to have no role except tobind to the receptor. The ligand is no metabolized to beneficial products, is notan intermediate in any kind of cellular activity, and has no enzymatic properties. Theonly function of the ligand shows up to be to change the properties of thereceptor, which climate signals to the cell that a details product is current inthe environment. Target cells regularly modify or degrade the ligand and, in sodoing, can modify or terminate their solution or the response of neighboringcells to the signal.

Hormones can Be Classified based on Their Solubility and also ReceptorLocation

Most hormones fall into three broad categories: (1) small lipophilic moleculesthat diffuse across the plasma membrane and interact withintracellular receptors; and also (2) hydrophilic or (3)lipophilic molecule that bind to cell-surface receptors (Figure 20-2). Recently, nitric oxide, agas, has actually been displayed to be a vital regulator regulating many to move responses.We comment on this vital regulator later in this chapter. Below we brieflydescribe the three main varieties of hormones; later on we discuss the mechanisms thatregulate their synthesis, release, and degradation.


Figure 20-2

Some hormones bind to intracellular receptors; others, tocell-surface receptors. (a) Steroid hormones, thyroxine, and retinoids, being lipophilic, aretransported by carrier proteins in the blood. ~ dissociationfrom this carriers, such hormones (more...)

Lipophilic Hormones with Intracellular Receptors

Many lipid-soluble hormones diffuse throughout the plasma membrane and interactwith receptors in the cytosol or nucleus. The result hormone-receptorcomplexes bind to transcription-control regions in DNA thereby affectingexpression of details genes (see Figure20-2a). Hormones of this type include the steroids (e.g.,cortisol, progesterone, estradiol, and testosterone), thyroxine, andretinoic acid (see Figure10-65).

All steroids space synthesized from cholesterol and also have similar chemicalskeletons. After cross the plasma membrane, steroid hormones interactwith intracellular receptors, forming complexes that have the right to increase ordecrease transcription of specific genes (see figure 10-68). These receptor-steroid complexes alsomay affect the security of details mRNAs. Steroids are efficient for hoursor days and also often influence the growth and differentiation that specifictissues. Because that example, estrogen and progesterone, the female sex hormones,stimulate the manufacturing of egg-white hormones in chickens and also cellproliferation in the hen oviduct. In mammals, estrogens stimulate expansion ofthe uterine wall in preparation for embryo implantation. In insects andcrustaceans, α-ecdysone (which is chemically regarded steroids)triggers the differentiation and also maturation of larvae; choose estrogens, itinduces the expression of particular gene products.


Thyroxine (tetraiodothyronine) andtriiodothyronine — the primary iodinatedcompounds in the body — are created in thethyroid by intracellular proteolysis of the iodinated protein thyroglobulinand immediately released right into the blood.


These two thyroid hormone stimulate enhanced expression of many cytosolicenzymes (e.g., liver hexokinase) that cata-lyze the catabolism that glucose,fats, and proteins and of mitochondrial enzymes the catalyze oxidative phosphorylation.

Retinoids room polyisoprenoid lipids acquired from retinol (vitamin A). Theyperform lot of regulatory functions in varied cellular processes.Retinoids manage cellular proliferation, differentiation, and also death, andthey have many clinical applications. Their diverse effects reflect, atleast in part, the multiplicity that retinoid derivatives, the existence oftwo different classes of receptor that kind heterodimers, and differencesin their cis-acting regulation sites ~ above DNA. During advancement retinoidsact as neighborhood mediators that cell-cell interaction. For instance, during theformation of motor neurons in the chick, one course of motor neuronsgenerates a retinoid signal i m sorry regulates the number and type ofneighboring motoneurons.

Water-Soluble Hormones v Cell-Surface Receptors

Because water-soluble signaling molecules cannot diffuse throughout the plasma membrane, lock all tie to cell-surface receptors. This big class ofcompounds is created of two groups: (1) peptide hormones, such together insulin, growth factors, andglucagon, which selection insize native a couple of amino acids to protein-size compounds, and (2) little chargedmolecules, such together epinephrine and histamine (see number 21-28), that are derived from amino acids andfunction together hormones and neurotransmitters.

Many water-soluble hormones induce a modification in the activity of one ormore enzymes already present in the target cell. In this case, the effectsof the surface-bound hormone generally are practically immediate, however persist because that ashort period only. This signals also can provide rise to transforms in gene expression that might persist for hours or days. In yet various other caseswater-soluble signal may result in irreversible changes, such together cellulardifferentiation.

Lipophilic Hormones with Cell-Surface Receptors

The primary lipid-soluble hormones that bind to cell-surface receptor arethe prostaglandins. There space at the very least 16different prostaglandins in nine different chemical classes, designatedPGA – PGI. Prostaglandins are component of aneven larger household of 20 carbon–containing hormone calledeicosanoid hormones. In addition to prostaglandins, they includeprostacyclins, thromboxanes, and leukotrienes. Eicosonoid hormone aresynthesized native a common precursor, arachidonic acid. Arachidonic acid isgenerated indigenous phospholipids and diacylglycerol.
In both vertebrates and also invertebrates,prostaglandins room synthesized and also secreted continuously by many types ofcells and rapidly broken down by enzymes in human body fluids.

Many prostaglandin act together localmediators throughout paracrine and also autocrine signaling and also are de-stroyed nearthe website of your synthesis. Lock mod-ulate the responses of various other hormonesand deserve to have profound results on numerous cellular processes. Certainprostaglandins cause blood platelets to aggregate and adhere to the walls ofblood vessels. Because platelets beat a crucial role in clotting blood andplugging leaks in blood vessels, these prostaglandin can influence the courseof vascular disease and wound healing; aspirin inhibits their synthesis byacetylating (and in order to irreversibly inhibiting) prostaglandinH2 synthase. Various other prostaglandins initiate the convulsion ofsmooth muscle cells; they accumulate in the uterus at the time of childbirthand show up to be essential in inducing uterine contraction.

Recent researches have displayed that a family of plant steroids, calledbrassinosteroids, regulates many elements ofdevelopment. These lipophilic compounds, like prostaglandins, action throughcell-surface receptors.

Cell-Surface receptor Belong come Four significant Classes

The different types of cell-surface receptor that communicate with water-solubleligands are schematically stood for in Figure20-3. Binding that ligand to several of these receptors inducessecond-messenger formation, conversely, ligand binding to rather does not. Forconvenience, we deserve to sort this receptors into four classes:

Figure 20-3

Four class of ligand-triggered cell-surface receptors. Usual ligands for each receptor type are detailed in parentheses. (a)G protein – linked receptors.Binding the ligand (maroon) triggers activation of a G protein, whichthen (more...)

The discussion in this chapter focuses primarily ~ above signaling pathways initiatedby G protein – coupled receptor (GPCRs) andreceptor tyrosine kinases (RTKs). The basic structure and also mechanism of actionof the intracellular receptors for steroid hormones are discussed in thing 10; ion networks are coveredin detail in Chapters 15 and 21; and details receptorserine/threonine kinases and also other developmentally relevant cell-surfacereceptors are explained in Chapter23.

Effects of numerous Hormones room Mediated by 2nd Messengers

The binding that ligands to countless cell-surface receptors leader to a short-livedincrease (or decrease) in the concentration that the intracellular signalingmolecules termed second messengers. This low-molecular-weight signalingmolecules encompass 3′,5′-cyclic AMP (cAMP);3′,5′-cyclic GMP (cGMP); 1,2-diacylglycerol (DAG); inositol1,4,5-trisphosphate (IP3); miscellaneous inositol phospholipids(phosphoinositides); and Ca2+ (Figure 20-4).

Figure 20-4

Structural recipe of four common intracellular secondmessengers. Their abbreviations space indicated. The calcium ion(Ca2+) and also several membrane-bound inositolphospholipids (phosphoinositides) also act as second messengers butare not shown (see Figure20-38). (more...)

The elevated intracellular concentration that one or much more second messengersfollowing hormone binding cause a rapid alteration in the activity of one ormore enzyme or nonenzymatic proteins. The metabolic functions regulated byhormone-induced 2nd messengers encompass uptake and utilization that glucose,storage and mobilization the fat, and secretion of cellular products. Theseintracellular molecules additionally control proliferation, differentiation, andsurvival of cells, in part by regulation the warrior of specific genes.The mode of activity of cAMP and also other second messengers is questioned in a latersection. Remove (or degradation) that a ligand or second messenger, orinactivation that the ligand-binding receptor, have the right to terminate the moving responseto one extracellular signal.

Other Conserved Proteins duty in Signal Transduction

In enhancement to cell-surface receptors and second messengers, several types ofconserved proteins role in signaltransduction pathways stimulated byextracellular signals. Here we introduce the three key classes the theseintracellular signaling proteins; their structures and also functions room describedin information in later sections.

GTPase switch Proteins

A big group of GTP-binding proteins act together molecularswitches in signal-transduction pathways. These proteins are turned“on” when bound come GTP and turned“off” when bound come GDP (Figure 20-5a). In the absence of a signal, theprotein is bound to GDP. Signal activate the relax of GDP, and also thesubsequent binding come GTP end GDP is favored by the greater concentrationsof GTP in the cell. The intrinsic GTPase activity of this GTP-bindingproteins hydrolyzes the bound GTP to GDP and Pi, thus convertingthe active type back to the inactive form. The kinetics that hydrolysisregulates the size of time the move is “on.”

Figure 20-5

Common intracellular signaling proteins. (a) GTP-binding proteins with GTPase activity function asmolecular switches. As soon as bound to GTP they are active; whenbound come GDP, they space inactive. They loss into two categories,trimeric G proteins and also Ras-like (more...)

There space two classes of GTPase move proteins: trimeric G proteins, whichas listed already are directly coupled to certain receptors, and monomericRas and also Ras-like proteins. Both classes contain regionsthat encourage the task of details effector proteins by directprotein-protein interactions. These areas are in their energetic conformationonly once the switch protein is bound come GTP. G proteins are coupleddirectly to caused receptors, whereas Ras is attached only indirect viaother proteins. The 2 classes of GTPbinding proteins additionally are regulated invery different ways.

Protein Kinases

Activation of all cell-surface receptors leader to changes in proteinphosphorylation v the activation of protein kinases(Figure 20-5b). In some caseskinases are component of the receptor itself, and in rather they are discovered in thecytosol or associated with the plasma membrane. Pet cells save on computer twotypes that protein kinases: those directed toward tyrosine and also those directedtoward either serine or threonine. The frameworks of the catalytic main point ofboth varieties are very similar. In general, protein kinases become active inresponse come the stimulation the signaling pathways. The catalytic activitiesof kinases room modulated by phosphorylation, by direct binding come otherproteins, and by changes in the level of various 2nd messengers. Theactivity the protein kinases is opposed by the task of proteinphosphatases, which eliminate phosphate groups from specificsubstrate proteins. The tasks of kinases and also phosphatases during cell cycle control are described in some information in chapter 13.

Adapter Proteins

Many signal-transduction pathways contain big multiprotein signalingcomplexes, which regularly are hosted together by adapterproteins (Figure20-5c). Adapter proteins execute not have actually catalytic activity, nor do theydirectly activate effector proteins. Rather, lock contain differentcombinations of domains, which function as docking website for various other proteins.For instance, different domains tie to phosphotyrosine residues (SH2 andPTB domains), proline-rich assignment (SH3 and also WW domains), phosphoinositides(PH domains), and also unique C-terminal sequences v a C-terminal hydrophobicresidue (PDZ domains). In some instances adapter proteins contain arrays that asingle binding domain or different combinations of domains. In addition,these binding domain names can be found alone or in various combinations inproteins comprise catalytic domains. These combinations provide enormouspotential for facility interplay and cross-talk in between different signalingpathways.

Common Signaling Pathways space Initiated by different Receptors in aClass

In general, various members the a particular class of receptors transducesignals by very conserved pathways. Moreover, analogies are found in thesignaling pathways linked with different receptor classes. Figure 20-6 illustrates the maincomponents the the an essential signaling pathways downstream native G protein – coupled receptors (GPCRs) and also receptortyrosine kinases (RTKs), the two receptor classes the we think about in information inthis chapter. Return a GTPase switch protein wake up in both varieties of pathways,its place in the pathway loved one to the receptor differs. 2nd messengersare an important components of many GPCR pathways and also some RTK pathways. Adapterproteins role in all RTK pathways yet not in the key GPCR pathways. Proteinkinases, however, pat a crucial role in every signaling pathways; eventually anactivated protein kinase phosphorylates one or an ext substrate proteins. Thenature that the substrate proteins, which encompass enzymes, microtubules, histones,and transcription factors, plays vital role in identify the cellularresponse come a certain signal in a details cell.

Figure 20-6

Schematic synopsis of typical signaling pathways downstream native Gprotein – coupled receptor (GPCRs)and receptor tyrosine kinases (RTKs). Hormone binding to the receptor initiates a series of events leadingto phosphorylation (more...)

The Synthesis, Release, and also Degradation the Hormones space Regulated

Because of their potent effects, hormones and neurotransmitters have to be carefullyregulated. The release and degradation of part signaling compounds room regulatedto develop rapid, temporary effects; rather to produce slower-acting butlonger-lasting effects (Table 20-1).In some cases, facility regulatory networks name: coordinates the levels of hormoneswhose results are interconnected.

Peptide Hormones and also Catecholamines

Organisms must have the ability to respond instantly to many changes in your internalor outside environment. Such quick responses space mediated mainly bypeptide hormones and the catecholamines epinephrine, norepinephrine, and also dopamine (seeFigure 21-28). The cell thatproduce this signaling molecules store them in secretory vesicles justunder the plasma membrane (see Figure21-30). The supply of stored, preformed signaling molecules issufficient because that 1 day in the situation of peptide hormones and for numerous days inthe instance of catecholamines. All peptide hormones, consisting of insulin andadrenocorticotropic hormone (ACTH), room synthesized as part of a longerpropolypeptide, which is cleaved by certain proteases to generate theactive molecule just after that is transported to a secretory vesicle (seeFigure 17-61).

Stimulation the signaling cells causes immediate exocytosis the the storedpeptide hormone or catecholamine right into the surrounding tool or the blood.Secreting cells additionally are engendered to synthesize the signaling molecule andreplenish the cell’s supply. Exit peptide hormone persist inthe blood for only seconds or minutes before being degraded by blood andtissue proteases. Released catecholamines are rapidly inactivated bydifferent enzymes or taken up by details cells (Section 21.4). The initialactions of this signaling molecules on target cells (the activation orinhibition of specific enzymes) also last just seconds or minutes. For this reason thecatecholamines and also some peptide hormones deserve to mediate quick responses thatare terminated through their own degradation.

Steroid Hormones, Thyroxine, and Retinoic Acid

The pathways for manufacturing steroid hormone from cholesterol show off 10 ormore enzymes. Steroid-producing cells, like those in the adrenal cortex,store a small supply the hormone precursor however none the the mature, activehormone. Once stimulated, the cells convert the precursor come the activehormone, which then diffuses across the plasma membrane right into the blood.Likewise, thyroglobulin, the iodinated precursor the thyroxine is save inthyroid follicles. Once cells lining this follicles space exposed tothyroid-stimulating hormone (TSH), they take up thyroglobulin; controlledproteolysis that this glycoprotein by lysosomal enzymes returns thyroxine,which is released right into the blood.

Because the signaling cells that create thyroxine and also steroid hormone storelittle of the energetic hormone, release of this hormones bring away from hours todays (see Table 20-1). Thesehormones, which room poorly soluble in aqueous solution, space transported inthe blood by carrier proteins; the tightly bound active hormones space notrapidly degraded. Thus, moving responses to thyroxine and also steroid hormonestake awhile come occur however persist from hours to days.

Retinol is save in the liver and also is found in high concentration in bloodin a complex with serum binding protein. As result of its lipophilic nature,retinol diffuses through the plasma membrane and also forms a complex with acytosolic retinol-binding protein called CRBP. Retinol is converted toretinal with the task of retinol dehydrogenase, and also retinal, in turn,is converted to retinoic acid by retinal dehydrogenase. Retinoic mountain canact as a signal in the cabinet in which it is produced, or it deserve to diffusethrough the plasma membrane to affect the advancement of neighboringcells. Retinoic mountain can likewise be additional modified enzymatically to change itssignaling specificity.

Feedback control of Hormone Levels

The synthetic and/or relax of numerous hormones are regulated bypositive or an adverse feedback. Thistype that regulation is particularly important in coordinating the action ofmultiple hormone on assorted cell varieties during growth and also differentiation.Often, the level of several hormones room interconnected through feedbackcircuits, in which alters in the level of one hormone impact the levels ofother hormones. One instance is the regulation the estrogen and also progesterone,steroid hormones the stimulate the growth and also differentiation of cell inthe endometrium, the organization lining the inner of the uterus. Transforms inthe endometrium prepare the organ to receive and nourish one embryo. Thelevels that both hormones are regulated by complex feedback circuits involvingseveral other hormones.

 Extracellular signal are often integratedinto complicated regulatory networks in which the synthesis, release, anddegradation of hormone are specifically regulated.

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