02.07.11Lecture 9:Cell Communication IMulticellular organisms need to coordinate cellular functions in different tissues Cell-to-cell communication is also used by single celled organisms to signal to other organismsBiologists have discovered several universal mechanisms of cellular regulationGeneral mechanism of cellular signaling1. Reception of signal2. Transduction of signal3. Cellular responseSignal transduction• Conversion of information from one form into anotherSignaling cascades perform 5 crucial functions1. Transduce signal into molecular form that can stimulate response2. Relay signal from point of reception to point of action in the cell3. Amplify the received signal4. Distribute the signal to influence several responses in parallel5. Each step is open to modulation by other signalsReceptors relay signals via intracellular signaling pathways• Individual cells respond to a limited set of signals for which they have receptors• A single cell may have 10 to 100,000 different receptors• Many signals acting together can elicit different cellular responses - a complex networkA signaling molecule may induce different responses in different cell typesExtracellular signals can act slowly or rapidlySignaling via chemical signals: direct communicationSignaling via chemical signals: local communicationSignaling via chemical signals: long-range communicationExtracellular signaling molecules fall into 2 classes:1. Molecules that are small enough or hydrophobic and pass through the membrane - directly activate intracellular receptors in the cytoplasm or nucleus of target cell2. Molecules that are too large or too hydrophilic to cross the plasma membrane - rely on membrane receptorsNitric oxide (NO) signals through a cytoplasmic receptor• NO is a chemically unstable gas• NO is a small, uncharged moleculeSteroid hormones signal through intracellular receptors• Steroid hormones are structurally similar to cholesterol• HydrophobicCell surface receptors fall into 3 main classes1. Ion-channel-linked receptorsConvert chemical signals ==> electrical signals2. G-protein-coupled receptors• Largest family of cell surface receptors•7 transmembrane α-helices• Extracellular N-term, intracellular C-term• C-terminus interacts with downstream effectorsMany signaling proteins act as molecular “switches”G proteins dissociate into 2 signaling complexes when activated1. Signal molecule binds GPCR2. Activated GPCR induces exchange of GDP for GTP on Gα subunit3. Gα dissociates from Gβγ4. Activated subunits diffuse within the plane of the membrane to activate downstream signaling moleculesThe Gα subunit inactivates itself by hydrolyzing its GTPG proteins regulate 2 types of targets1. Ion channel opening (I.e. K+channels in heart muscle cells)2. Membrane-bound enzymes (e.g. adenylyl cyclase, phospholipases)Some G proteins regulate ion channels• Acetylcholine slows the heart• Receptor activation ==> dissociation of Gα and Gβγ•Gβγ opens K+ channels to decrease the amplitude of contractionSome G proteins regulate membrane-bound enzymes to make second messengersTwo most common enzymes activated by G proteins• Adenylyl cyclase - converts ATP into cyclic AMP (cAMP)• Phospholipase C - cleaves a lipid (isositol phospholipid) into isositol-1,4,5-trisphosphate (IP3, a hydrophilic sugar) and diacylglycerol (DAG, a lipid in the membrane)Cyclic AMP (cAMP) is a common second messenger• cAMP is generated from ATP by adenylyl cyclase• cAMP is degraded by cAMP phosphodiesterase• Caffeine inhibits phosphodiesterase• cAMP activates cAMP-dependent protein kinase (PKA)The activation of cyclic-AMP -dependent protein kinase (PKA)Intracellular cAMP can activate gene transcriptionCalcium ion concentrations are kept low in the cytosol by calcium pumpsPhospholipase C activates 2 signaling
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