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Rose-Hulman CHEM 330 - Signal transduction

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Copyright © 2000-2003 Mark Brandt, Ph.D.93Signal transductionIn order to interact properly with their environment, cells need to allowinformation as well as molecules to cross their cell membranes. Information inmany single-celled and all multicellular organisms is transmitted in the form ofmolecules. However, the molecule itself does not contain the information. Themolecule only carries the fact of the information, not the information itself. Theway the cell acts on the arrival of the information determines the informationcontent; in effect, the cell itself decides how to respond to the information.Glucose (in most cells) is not!a signaling molecule, because the cell merely usesglucose as a metabolite, while insulin is a signaling molecule, because its primaryfunction is to modify cellular responses, rather than to act as a source of energy orbiosynthetic intermediates.The term “signal transduction” refers to the conversion of the information carried bysignaling molecules into changes in cellular activities.Requirements for signal transduction1) Signal transduction requires a receptor, a cellular protein thatrecognizes the signaling molecule.In the absence of the receptor, the ligand has no effect. Cells that lackreceptors for a given ligand do not respond to that ligand. (Note: a ligand is asignaling molecule that binds to a particular receptor.)Receptors must bind the signaling molecule with high affinity. Receptorsmust bind ligand at physiological ligand concentrations. If the Kd for the ligand is10 µM while the physiological concentration of the ligand is 0.1 nM, the protein isnot the receptor for that ligand. For example, the estrogen receptor has a Kd forestradiol of 0.1 – 0.2 nM; in mature females, the serum concentration of estradiolusually varies between about 0.1 and 1.3 nM depending on the phase of themenstrual cycle.Receptors must exhibit specificity for the ligand. Receptorsshould bind ligands, but should not bind closely related molecules.This is not an absolute requirement, and in most cases, high enoughconcentrations of competing ligands may result in receptor bindingby competitor. However, most receptors are able to distinguishfairly similar molecules; a receptor typically binds the actualhormone with 10-fold to 10,000-fold higher affinity than it exhibitsfor chemically related molecules. For example, the estrogen receptorbinds testosterone with about 50,000-fold lower affinity than it doesestradiol, although the molecules are structurally similar.Receptors must exhibit a finite capacity for the ligand (usually, the bindingof one ligand molecule per receptor molecule). The requirement for finite capacityarose from pharmacological studies performed before the isolation of the receptorproteins. Some compounds bind glass tubes and other experimental systemcomponents with high affinity and stereochemical specificity; glass tubes typicallyCopyright © 2000-2003 Mark Brandt, Ph.D.94have vast numbers of binding sites, while cells generally do not.Ligand binding must elicit a direct biological effect. Some non-receptorproteins have high affinity for ligands, but ligand binding to these proteins has noeffect on cellular functioning, and therefore these proteins are not receptors.2) Signal transduction requires a mechanism for linking ligand bindingto biological changes within a cell.The hormone is the “first messenger”. In most cases, the binding of the hormone tothe receptor elicits the release of a “second messenger”: a compound that acts likean intracellular hormone. The release of the second messenger is the first step intransmitting the signal from the outside to the inside of the cell.Second messengers allow amplification of a signal; one hormone moleculebinding to one receptor can result in the production of many second messengermolecules. Second messengers allow the convergence of multiple pathways,because more than one second messenger pathway can affect specific cellularenzymes. Second messengers also allow more than one hormone to have similareffects in some cell types, because both hormones result in production of the samesecond messenger. Second messengers also allow modulation of a signal; onehormone can alter the response to a second hormone by affecting the production ofthe second messenger.3) Signal transduction results in a variety of types of biological effects.Hormonal effects can be mediated by one of two major processes. The first, andfaster process is an alteration in the activity of existing proteins. This caninvolve the opening or closing of ion channels, binding of a second messengercausing activation or inhibition of an enzyme, or the covalent modification ofexisting proteins (especially phosphorylation or dephosphorylation of enzymes)resulting in altered enzymatic activity. The second, and slower process is thealteration in the amount of a protein. This is usually the result of activation orinhibition of gene transcription; it may also be due to changes in the rate ofdegradation of the protein.4) Signal transduction pathways have at least one mechanism forturning the signal off.The most obvious method for turning off a signal is the dissociation of the ligandfrom the receptor. This can be the result of a cellular process, or of a decrease in thecirculating concentration of the ligand. Most second messengers have short half-lives within the cell, and therefore when the hormone dissociates, the secondmessenger levels decrease, terminating the signal. However, in some cases, thesignaling molecule concentration remains high for prolonged periods. For manycells, chronic response to a signal results in deleterious changes to that cell; thesecells therefore need some mechanism for reducing their response to the signal inspite of continued presence of the signal. Cells have two mechanisms for decreasingtheir responsiveness to a hormone: down-regulation and desensitization. Down-regulation is the result of a decreased concentration of the receptor; fewerreceptors means a smaller response to a signal. Desensitization is the result of adecrease in the cellular response to a signal, either as a result of decreased


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