2 Overview No cell lives in isolation In all multicellular organisms, survival depends on an elaborate intercellular communication network that coordinates the growth, differentiation, and metabolism of the multitude of cells in diverse tissues and organs.Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity, and diabetes. By understanding cell signaling, diseases can be treated effectively and, theoretically, artificial tissues could be built.
3 Cells within small groups often communicate by direct cell-cell contact. Specialized junctions in the plasma membranes of adjacent cells permit them to exchange small molecules and to coordinate metabolic responses; other junctions between adjacent cells determine the shape and rigidity of many tissues.In addition, the establishment of specific cell-cell interactions between different types of cells is a necessary step in the development of many tissues. In some cases a particular protein on one cell binds to a receptor protein on the surface of an adjacent target cell, triggering its differentiation.
5 In multicellular organisms Signal molecules produce responses in target cells that have receptors.In multicellular organismsChemicalsSmall molecules (aa., lipid derivatives)PeptidesproteinsSome diffuse and bind to intracellular receptorsSteroids, retinoids, thyroxine
7 Signal transductionOverall processes converting a signal into cellular responses
8 Cell Signaling Steps involved are: Synthesis Release from signaling cellsTransport to target cellsBinding to receptor and activationSignal transduction by activated receptorSpecific changesRemoval of signal (termination)
9 Receptor activation Secreted or membrane bound molecules Hormones, growth factors, neurotransmitters, pheromonesChanges in the concentration of metabolitesOxygen or nutrientsPhysical stimuliLight, touch, heat
10 Three types of signaling in animals EndocrinehormonesParacrineNeurotransmittersGrowth factorsAutocrineGrowth factors (cultured cells, tumor cells)
11 Ligand binding and effector specificity Each receptor binds only a single ligand or a group of closely related molecules. However, many signaling molecules bind to multiple types of receptorsAcetylcholine binds to different receptors on muscle cells (contraction), heart muscle cells (inhibition of contraction) and pancreas acinar cells (exocytosis of secretory granules), respectively
12 Different receptors of the same class that bind different ligands generate the same cellular responseIn liver, ACTH, epinephrine and glucagon bind to different GPCRs; but all three activate the same signaling pathway (cAMP)
13 Intracellular signal transduction Many receptors transmit signals via second messengersThey rapidly alter the activity of enzymes or non-enzymatic proteinsCa2+ triggers contraction in muscle cellsExocytosis of secretory vesicles in endocrine cellscAMP generates different metabolic changes in different type of cells
14 Regulation of signaling External signal decreasesDegradation of second mesengerDesensitization to prolonged signalingReceptor endocytosisModulation of receptor activityPhosphorylationBinding to other proteins
16 Hormones Can Be Classified Based on Their Solubility and Receptor Location Most hormones fall into three broad categories:(1) small lipophilic molecules that diffuse across the plasma membrane and interact with intracellular receptors;(2) hydrophilic or (3) lipophilic molecules that bind to cell-surface receptors.Recently, nitric oxide, a gas, has been shown to be a key regulator controlling many cellular responses
17 Classification of receptors Intracellular receptors (for lipid soluble messengers)function in the nucleus as transcription factors to alter the rate of transcription of particular genes.Plasma membrane receptors (for lipid insoluble messengers)Receptors function as ion channelsreceptors function as enzymes or are closely associated with cytoplasmic enzymesreceptors that activate G proteins which in turn act upon effector proteins, either ion channels or enzymes, in the plasma membrane.
18 Hormones bind to intracellular receptors and to cell-surface receptors
20 Intracellular Receptors Extracellular signal molecules are small, lipid-soluble hormones such as steroid hormones, retinoids, thyroid hormones, Vitamin D. (Made from cholesterol)These hormones diffuse through plasma and nuclear membranes and interact directly with the transcription factors they control.
22 Sequence similarities and three functional regions N-terminal region of variable length ( aa); in some receptors portions of this region act as activation domainAt the center, DNA binding domain, made of a repeat of C4-zinc finger motifNear the C-terminal end, an hormone binding domain, which may act as an activation or repression domain.
24 Nuclear receptor response elements Some characteristic sites of DNA are called response elements and can bind several nuclear receptors.These repeat regions are arranged either as an invert repeat, or direct repeat.Inverted repeat: glucocorticoid response element; estrogen response elementRepeats are separated by any three bases, implicating symmetrical binding of the receptor homodimer to DNA
26 Receptors for vitaminD, retinoic acid and thyroid hormone bind to direct repeats as heterodimers, Second component of the heterdimer is RXR monomer (i.e, RXR-RAR; RXR-VDR)The specifity of the binding is determined by the spacing between repeats.
27 Regulation of transcription activity Regulatory mechanisms differ for hetero-dimeric and homodimeric receptorsHeterodimeric receptors are exclusively nuclear; without ligand, they repress transcription by binding to their cognate sites in DNAThey do so by histone deacetylation
28 Homodimeric receptors are cytoplasmic in the absence of ligands. Hormone binding leads to nuclear translocation of receptorsAbsence of hormone causes the aggregation of receptor as a complex with inhibitor proteins, such as Hsp90