8 Регуляция экспрессии генов. Система передачи сигнала (1160077)
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Лекция 8.Регуляция экспрессии генов.Система передачи сигналаChapter 22 Integration and Hormonal Regulation of Mammalian Metabolism773Ion Channels Are Gated by Ligands and byMembrane PotentialIn a fourth class of signal transducers, receptors are coupled directly orindirectly to ion channels in the plasma membrane. The best-understood example of such a receptor is the nicotinic acetylcholine receptor, which responds to the neurotransmitter acetylcholine.
It isfound in the postsynaptic cells in certain nerve synapses (Fig. 22-34)and in the junction between a muscle fiber and the neuron that controls it. The acetylcholine receptor complex (Mr 250,000) is composed offour different polypeptide chains, one of which is present in two copies.The transmembrane arrangement of these five chains provides a hydrophilic channel through which ions can traverse the lipid bilayer.When acetylcholine released from the presynaptic nerve ending bindsVoltage- +gated Na+channel (siteof action oftetrodotoxinandsaxitoxin)Axon ofpresynapticneuronActionpotentialVoltage-' 2+ +Sgated Ca AchannelSecretoryvesicles containingacetylcholineSynapticcleftCell body ofpostsynapticneuronAcetylcholine receptor-ionchannels (site of action oftubocurarine, cobrotoxin,bungarotoxin)/Figure 22-34 Role of voltage-gated and ligandgated ion channels in passage of an electrical signalbetween two neurons.
Initially, the plasma membrane of the presynaptic neuron is polarized, withthe inside negative; this results from the action ofthe electrogenic Na+K+ ATPase, which pumps threeNa+ outward for every two K+ pumped into theneuron (see Fig. 10-22). (T) A stimulus to this neuron causes an action potential to move downwardalong its axon (white arrow). The opening of onevoltage-gated Na+ channel allows NaT entry, andthe resulting local depolarization causes the adjacent Na+ channel to open, and so on.
The directionality of movement of the action potential is ensuredby the brief refractory period that follows the opening of each voltage-gated Na+ channel. (2) Whenthis wave of depolarization reaches the axon tip,voltage-gated Ca2+ channels open, allowing Ca2^entry into the presynaptic neuron. (3) The resultingincrease in internal [Ca2+] triggers exocytosis of theneurotransmitter acetylcholine into the space between the neurons (synaptic cleft).
(4) Acetylcholinebinds to its specific receptor in the plasma membrane of the cell body of the postsynaptic neuron,causing the ligand-gated ion channel that is part ofthe receptor to open. (5) Extracellular Na^ and K+enter through this channel, depolarizing the postsynaptic cell. The electrical signal has thus passedto the postsynaptic cell, and will move along itsaxon to a third neuron by this same sequence ofevents.
The effects of the toxins shown in parentheses are discussed on p. 774.CH 3 -CPXActionpotential/IO—CH 2 -CH 2 -N(CH 3 ) 3Acetylcholine774Part III Bioenergetics and Metabolismto its receptor in the postsynaptic cell (Fig. 22-34), the receptor-ionchannel opens, allowing transmembrane passage of Na+ and K+ ions(pp. 292-293). The receptor is therefore referred to as a ligand-gatedion channel. The resulting depolarization of the postsynaptic membrane triggers muscle contraction or initiates an action potential in thepostsynaptic neuron.The action potential is a wave of transient depolarization thatsweeps the neuron from the site of the initial stimulus (in the cell bodyof the neuron), along the long, thin cytoplasmic extension (axon), to thenext synapse. Essential to this signaling mechanism are several typesof "voltage-gated" ion channels in the plasma membrane of the neuron.These channels, formed by transmembrane proteins, open and close inresponse to changes in the transmembrane electrical potential.
Alongthe entire length of the axon are voltage-gated Na+ channels (Fig.22-34), which are closed when the membrane is polarized, but openbriefly when the membrane potential is reduced (i.e., during depolarization). After each opening of a Na+ channel there follows a briefrefractory period during which the channel cannot open again, andthus a unidirectional wave of depolarization sweeps from the nerve cellbody toward the end of the axon.At the distal tip of the neuron are voltage-gated Ca2+ channels.When the wave of depolarization reaches these channels they open,letting Ca2+ enter from the extracellular space and triggering acetylcholine release into the synaptic cleft (Fig.
22-34). Acetylcholine diffuses to the postsynaptic cell, where it binds to acetylcholine receptors;thus the message is passed to the next cell in the circuit.Toxins, Oncogenes, and Tumor PromotersInterfere with Signal TransductionsBiochemical studies of signal transductions have led to an improvedunderstanding of the pathological effects of toxins produced by the bacteria that cause cholera and pertussis (whooping cough). Both toxinsare enzymes that interfere with normal signal transductions in thehost animal. Cholera toxin, secreted by Vibrio cholerae found in contaminated drinking water, catalyzes the transfer of ADP-ribose fromNAD+ to the a subunit of Gs, blocking its GTPase activity (Fig.
22-26)and thereby rendering it permanently activated (Fig. 22-35). This results in continuous activation of the adenylate cyclase of intestinalepithelial cells, and the resultant high concentration of cAMP triggerscontinual secretion of Cl~, HCO3 , and water into the intestinal lumen.The resulting dehydration and electrolyte loss are the major pathologies in cholera. The pertussis toxin produced by Bordetella pertussiscatalyzes ADP-ribosylation of Gi? preventing GDP displacement byGTP and blocking inhibition of adenylate cyclase by Gi; this defectproduces the symptoms of whooping cough, including hypersensitivityto histamines and lowered blood glucose.The critical importance of ligand- and voltage-gated ion channelsin nerve signal conduction as described above is clear from the effectsof several naturally occurring toxins.
Tubocurarine, the active component of curare (used as an arrow poison in the Amazon), and toxinsfrom snake venoms (cobrotoxin and bungarotoxin), block the acetylcholine receptor or prevent the opening of its ion channel (Fig. 2234). By blocking signals from nerves to muscles, these toxins causeparalysis and death. Tetrodotoxin (from the internal organs of pufferfish) and saxitoxin (produced by the marine dinoflagellate that occa-Chapter 22 Integration and Hormonal Regulation of Mammalian Metabolism7750IIi•Arg-NH2+i°°IIII- _CH 2 -O-P—0—P-0- Rib — Adenine,||k y ^^N^OH\L__J/HNormal Gs: GTPase activityterminates the signalfrom receptor to adenylatecyclase.HOOHNAD+OIcholeratoxin !C—NH 2OCH9—O—P—O—P—O — Rib — AdenineIO"O"Arg-NH/°ADP-ribosylated Gs:GTPase activity is inactivated;Gs constantly activatesadenylate cyclase.OOHsionally causes "red tides") are also deadly poisons, which block neurotransmission by preventing the opening of Na + channels.Tumors and cancer are the result of uncontrolled cell division.
Normally, cell division is highly regulated by a family of growth factors,proteins that cause resting cells to undergo cell division and, in somecases, differentiation. Some growth factors are cell type-specific, stimulating division of only those cells with appropriate receptors; othergrowth factors are more general in their effects.
Among the well-studied growth factors are epidermal growth factor (EGF), nerve growthfactor (NGF), fibroblast growth factor (FGF), platelet-derived growthfactor (PDGF), erythropoietin, and a family of proteins called lymphokines, which includes interleukins (IL-1, IL-2, etc.) and interferon y.There are also extracellular factors that antagonize the effects ofgrowth factors, slowing or preventing cell division; transforminggrowth factor )8 (TGF/3) and tumor necrosis factor (TNF) are such factors.These extracellular signals act through cell-surface receptors verysimilar to those for hormones, and by similar mechanisms: the production of intracellular second messengers, protein phosphorylation, andultimately, alteration of gene expression.It is becoming clear that many types of cancer are the result ofabnormal signal-transducing proteins, which lead to continual production of the signal for cell division.
The mutated genes that encode thesedefective signaling proteins are oncogenes. (Oncogenes, and genefunction in general, are discussed in Chapter 25.) Oncogenes were originally discovered in tumor-causing viruses, then later found to beclosely similar to or derived from genes present in the animal hostcells. Most likely, these viral genes originated from normal host genes(proto-oncogenes) that encode growth-regulating proteins. During certain types of viral infections, these DNA sequences can be copied by thevirus and incorporated into its genome (Fig. 22-36). At some pointduring the cycle of viral infection, the gene can become defective as aADP-riboseFigure 22-35 The toxins produced by the bacteriathat cause cholera and whooping cough (pertussis)are enzymes that catalyze transfer of the ADPribose moiety of NAD^ to an Arg residue of G proteins: Gs in the case of cholera (as shown here) andGj in whooping cough.
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