Slide 1Important Concepts in Signal TransductionCells respond to the environment: Signal TransductionSlide 4Steps of Signal TransductionSlide 6Slide 7The biochemical basis for signal transduction involves three primary mechanisms:Slide 9Small molecules act as diffusible signalsSlide 11One of the best characterized second messengers is cyclic AMP (cAMP).Slide 13Another second messenger important in signal transduction is cyclic GMP (cGMP)Slide 15Some Other Second Messengers: diacylglycerol (DAG), inositol 1,4,5-trisphosphate (IP3) and calcium ion (Ca2+).Slide 17Slide 18Slide 19Slide 20β-Adrenergic receptor signal transduction pathwayInactive form of G protein heterotrimer binds GDPG Protein ActivationThe human genome contains 15 α, 5 β and 10 γ subunits, leading to many different possible combinations (~1000) and functionsThe activated Gα subunit binds to other proteins to activate themExamples from the adrenergic systemsSlide 27Slide 28Slide 29How does cAMP binding activate the phosphorylating function of protein kinase A?Stimulation of PKA signaling events in liver cells by epinephrineStimulation of PKA in liver cells by epinephrineSlide 33Activation of phospholipase CPLC produces second messengers DAG and IP3Function of second messengers IP3 & DAGStimulation of PKC signaling events in liver cells by epinephrineG proteins reset themselvesDon’t forget the 7TM receptor, it must be reset as well, or it activates more G proteinSummary of G protein coupled receptor signalingWhat happens when receptors aren’t reset?Slide 42Lecture 22Signal Transduction 1Important Concepts in Signal Transduction•Primary messengers•Membrane receptors•Second messengers•Amplification•Signal termination•7TM receptors•G proteins•Adenylate cyclase - Protein Kinase A•Phospholipase C- Protein Kinase C, Ca2+ ChannelsCells respond to the environment:Signal TransductionThe term signal transduction refers to the biochemical mechanism responsible for “transmitting” extracellular signals inside the cell, which ultimately lead to the activation of target proteins that control metabolic pathways or regulate gene expression. Courtesy: Roger Miesfeld1. Signal molecule (primary messenger, first messenger, ligand) travels to the cell.2. Primary messenger binds to the extracellular domain of a receptor protein and initiates a structural change in the receptor which is propagated across the membrane.–Membrane receptors sense the stimulus and transfer info across the membrane.–Exception: some molecules, for example steroid hormones, move across membranes, bind to proteins and act, generally at the nucleus. –Most molecules are too polar or too large to cross the membrane, so the stimulus does not enter without membrane receptors. –Generally, receptors are intrinsic (integral) membrane proteins with extra- and intracellular domains.Steps of Signal Transduction3. Receptor protein stimulates signaling proteins 4. Second messengers amplify the signal–Free to diffuse–Cross talk between pathways exists5. Second messengers bind to additional signaling proteins6. Signal is propagated, often by a protein kinase cascadeSteps of Signal Transduction7. Target proteins are affected (activated, inhibited)–Transcription factors–Metabolic enzymes–Cytoskeletal proteins–Transport proteins–Etc.8. Signal is terminated–PhosphatasesSteps of Signal TransductionThe biochemical basis for signal transduction involves three primary mechanisms:1) protein conformational changes2) covalent protein modifications3) altered rates of gene expressionFirst/primary messengers are small diffusible biomolecules. These can be produced through endocrine mechanisms and act at a distance. Or they can function locally as paracrine or autocrine signals.Courtesy: Roger MiesfeldSmall molecules act as diffusible signalsFirst/Primary MessengersHuman growth hormone and insulin are peptide hormonesCortisol is a steroid that is derived from cholesterolEpinephrine, also known as adrenaline, is a derived from the amino acid tyrosineAcetylcholine is a neurotransmitter that binds the acetylcholine receptor NO is produced by deamination of L-arginineSmall molecules act as diffusible signalsSecond MessengersSecond messengers amplify the receptor-generated signalFine tuningRapid production of maximum responseProduced by the enzyme adenylate cyclase from ATP. Receptor activation of adenylate (adenylyl) cyclase generates large amounts of cAMP, which in turn, binds to and activates downstream signaling proteins such as cAMP dependent protein kinase A (PKA). Importantly, the intracellular concentration of cAMP is carefully controlled by the relative levels of receptor-activated adenylate cyclase and soluble forms of cAMP phosphodiesterase (PDE) which converts cAMP to AMP.Courtesy: Roger MiesfeldOne of the best characterized second messengers is cyclic AMP (cAMP).The intracellular concentration of cAMP is carefully controlledRelative levels of receptor-activated adenylate cyclase and soluble forms of cAMP phosphodiesterase (PDE) which converts cAMP to AMP.Courtesy: Roger MiesfeldProduced from GTP by the enzyme guanylyl cyclase. The cGMP analog Sildenafil, also know as Viagra, is used to treat sexual dysfunction by inhibiting the activity of cGMP phosphodiesterase (PDE). The molecular structure of sildenafil is similar to cGMP and binds tightly to cGMP PDE.Courtesy: Roger MiesfeldAnother second messenger important in signal transduction is cyclic GMP (cGMP)Courtesy: Roger MiesfeldThe Kissing Bug, Rhodnius prolixus, delivers NO to their victims by injecting heme-containing proteins called nitrophorins that carry NO into the wound along with their saliva.Intracellular levels of DAG, IP3 and Ca2+ are controlled by the activity of a membrane associated enzyme called phospholipase C (PLC). Receptor-mediated activation of phospholipase C leads to cleavage of the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) to form DAG and IP3. Courtesy: Roger MiesfeldSome Other Second Messengers: diacylglycerol (DAG), inositol 1,4,5-trisphosphate (IP3) and calcium ion (Ca2+).The term signal transduction refers to the biochemical mechanism responsible for “transmitting” extracellular signals inside the cell, which ultimately lead to the activation of target proteins that control metabolic pathways or regulate gene expression. Courtesy: Roger Miesfeld5 Major classes of receptor proteins:the gatekeepers of the cell Courtesy: Roger
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