Signal transduction In order to interact properly with their environment cells need to allow information as well as molecules to cross their cell membranes Information in many single celled and all multicellular organisms is transmitted in the form of molecules However the molecule itself does not contain the information The molecule only carries the fact of the information not the information itself The way the cell acts on the arrival of the information determines the information content 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 uses glucose as a metabolite while insulin is a signaling molecule because its primary function is to modify cellular responses rather than to act as a source of energy or biosynthetic intermediates The term signal transduction refers to the conversion of the information carried by signaling molecules into changes in cellular activities Requirements for signal transduction 1 Signal transduction requires a receptor a cellular protein that recognizes the signaling molecule In the absence of the receptor the ligand has no effect Cells that lack receptors for a given ligand do not respond to that ligand Note a ligand is a signaling molecule that binds to a particular receptor Receptors must bind the signaling molecule with high affinity Receptors must bind ligand at physiological ligand concentrations If the Kd for the ligand is 10 M while the physiological concentration of the ligand is 0 1 nM the protein is not the receptor for that ligand For example the estrogen receptor has a Kd for estradiol of 0 1 0 2 nM in mature females the serum concentration of estradiol usually varies between about 0 1 and 1 3 nM depending on the phase of the menstrual cycle Receptors must exhibit specificity for the ligand Receptors should bind ligands but should not bind closely related molecules This is not an absolute requirement and in most cases high enough concentrations of competing ligands may result in receptor binding by competitor However most receptors are able to distinguish fairly similar molecules a receptor typically binds the actual hormone with 10 fold to 10 000 fold higher affinity than it exhibits for chemically related molecules For example the estrogen receptor binds testosterone with about 50 000 fold lower affinity than it does estradiol although the molecules are structurally similar Receptors must exhibit a finite capacity for the ligand usually the binding of one ligand molecule per receptor molecule The requirement for finite capacity arose from pharmacological studies performed before the isolation of the receptor proteins Some compounds bind glass tubes and other experimental system components with high affinity and stereochemical specificity glass tubes typically Copyright 2000 2003 Mark Brandt Ph D 93 have vast numbers of binding sites while cells generally do not Ligand binding must elicit a direct biological effect Some non receptor proteins have high affinity for ligands but ligand binding to these proteins has no effect on cellular functioning and therefore these proteins are not receptors 2 Signal transduction requires a mechanism for linking ligand binding to biological changes within a cell The hormone is the first messenger In most cases the binding of the hormone to the receptor elicits the release of a second messenger a compound that acts like an intracellular hormone The release of the second messenger is the first step in transmitting the signal from the outside to the inside of the cell Second messengers allow amplification of a signal one hormone molecule binding to one receptor can result in the production of many second messenger molecules Second messengers allow the convergence of multiple pathways because more than one second messenger pathway can affect specific cellular enzymes Second messengers also allow more than one hormone to have similar effects in some cell types because both hormones result in production of the same second messenger Second messengers also allow modulation of a signal one hormone can alter the response to a second hormone by affecting the production of the 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 and faster process is an alteration in the activity of existing proteins This can involve the opening or closing of ion channels binding of a second messenger causing activation or inhibition of an enzyme or the covalent modification of existing proteins especially phosphorylation or dephosphorylation of enzymes resulting in altered enzymatic activity The second and slower process is the alteration in the amount of a protein This is usually the result of activation or inhibition of gene transcription it may also be due to changes in the rate of degradation of the protein 4 Signal transduction pathways have at least one mechanism for turning the signal off The most obvious method for turning off a signal is the dissociation of the ligand from the receptor This can be the result of a cellular process or of a decrease in the circulating concentration of the ligand Most second messengers have short halflives within the cell and therefore when the hormone dissociates the second messenger levels decrease terminating the signal However in some cases the signaling molecule concentration remains high for prolonged periods For many cells chronic response to a signal results in deleterious changes to that cell these cells therefore need some mechanism for reducing their response to the signal in spite of continued presence of the signal Cells have two mechanisms for decreasing their responsiveness to a hormone down regulation and desensitization Downregulation is the result of a decreased concentration of the receptor fewer receptors means a smaller response to a signal Desensitization is the result of a decrease in the cellular response to a signal either as a result of decreased amount Copyright 2000 2003 Mark Brandt Ph D 94 of or decreased response to a second messenger These definitions and features of receptors apply to all systems that use secreted signaling molecules Neurotransmitters used in nervous system cytokines used by immune system and hormones and growth factors all bind to receptors Details of these signaling molecules and receptor types vary depending on the cell type and the