Physiology Unit 1 CELL SIGNALING: CHEMICAL MESSENGERS AND SIGNAL TRANSDUCTION PATHWAYS Cell Communica4on •  Homeosta4c mechanisms maintain a normal balance of the body’s internal environment •  Opera4on of control systems require cells to be able to communicate with each other •  Intercellular communica4on is mostly by chemical messengers –  Ligands •  NeurotransmiCers – Rapid – Short distance •  Hormones – Slower – Longer distance •  Gases Ÿ Paracrine Agents − Released by cell − Binds to neighboring cells Ÿ Autocrine agents − Released by cell − Binds to self cell Receptors •  Cell must have a mechanism to detect a chemical messenger •  Receptor protein has a binding site for the chemical messenger •  Signal transduc.on pathways converts chemical signals to a biologically meaningful response Characteris4cs of Receptors •  Specificity –  Single messenger –  Mul4ple messengers •  Affinity •  Satura4on •  Compe44on –  Antagonists –  Agonists Compe44on •  Messengers or molecules with a similar structure compete for binding sites on receptors •  Antagonists –  Blocks the endogenous messenger and prevents the response •  Agonists –  Binds to receptor and triggers the cells response –  Mimics endogenous messenger Regula4on of Receptors •  Receptors are subject to physiological regula4on –  Number of receptors –  Affinity of receptors •  Down-­‐regula4on –  Persistent, high [chemical messenger] –  Desensi4zing –  Local nega4ve feedback •  Up-­‐regula4on –  Prolonged, low [chemical messenger] –  Supersensi4vity Signal Transduc4on Pathways •  Sequence of events from binding of a chemical messenger and the cells response •  Receptor ac4va4on is the ini4al step –  Messenger-­‐receptor binding causes a conforma4on change in the receptor –  Response may change (alter ac4vity/transla4on of cell proteins) –  Permeability –  Transport proper4es –  Voltage change in the membrane –  Cell metabolism –  Cell secretory ac4vity –  Cells contrac4le ac4vity Lipid Soluble Messengers •  Messengers bind to intracellular receptors •  Lipid soluble •  Messengers are inac4ve un4l bound to a receptor •  Ac4vated receptor acts as a transcrip.on factor •  Cor4sol •  Steroid hormones •  Thyroid hormones Water Soluble Messengers •  Binds to receptor on the extracellular surface of the plasma membrane •  Water soluble messengers –  Pep4de hormones –  NeurotransmiCers –  Paracrine/autocrine compounds •  Common mechanisms of receptors 1.
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Ligand-­‐gated ion channels Receptors func4on as enzymes (tyrosine kinases) Bind to and ac4vate cytoplasmic JAK kinases G-­‐protein coupled receptors that ac4vate G-­‐proteins which then act on ion channels or enzymes in the plasma membrane Water Soluble Messengers Pathway Components •  Pathway Components 1.  Receptor Ac4va4on •  Water soluble chemical messenger binds to a plasma membrane receptor 2.  Receptor ac4va4on generates a second chemical messenger in the cytoplasm 3.  Signal transduc4on: a series of chemical reac4ons that result in the cells response •  Protein kinase –  Any enzyme that phosphorylates other enzymes or proteins by transferring a phosphate group from ATP –  Ac4vates the enzyme or protein •  Changes the conforma4on of the phosphorylated protein Ligand Gated Ion Channels •  Receptor ac4va4on opens an ion channel •  Increases membrane permeability of that ion •  Ion diffuses across the plasma membrane •  Changes membrane poten4al Receptors That Func4on as Enzymes •  Intrinsic enzyme ac4vity •  Receptor tyrosine kinases •  Influence •  cell prolifera4on •  Cell differen4a4on •  apoptosis •  Receptor ac4va4on includes ac4va4on of the enzyme por4on –  The receptor phosphorylates its own tyrosine groups –  Phosphotyrosines serve as docking sites for cytoplasmic proteins that ac4vate signaling pathways inside the cell •  Ac4vate cytoplasmic proteins by phosphoryla4on Receptors That Ac4vate JAK Kinases •  Receptor ac4va4on ac4vates the associated JAK kinase •  JAK kinases phosphorylate transcrip4on factors •  Cytokines ac4vate JAK kinase receptors •  Proteins secreted by cells of the immune system G-­‐Protein-­‐Coupled Receptors •  Very common •  G-­‐protein complex bound to a receptor •  Receptor ac4va4on results in dissocia4on of the α sub-­‐unit •  α-­‐sub-­‐unit ac4vates an ion channel or an enzyme in the plasma membrane Cyclic AMP (cAMP) 2nd messenger •  Source –  1st messenger ac4vates a G-­‐protein coupled receptor –  G-­‐protein ac4vates adenylyl cyclase •  Adenylyl cyclase catalyzes the conversion of ATP to cAMP •  Ac4on: –  cAMP ac4vates cAMP-­‐dependent protein kinase A •  Protein kinase A ac4vates a large number of different proteins •  Ini4ates an amplifica4on cascade –  cAMP may also de-­‐ac4vate enzymes •  Rate limi4ng step in glycogen synthesis Cyclic AMP (cAMP) 2nd messenger Phosphodiesterase deac4vates cAMP to AMP Signal Amplifica4on by cAMP Diacylgylerol (DAG) 2nd messenger •  Source –  1st messenger ac4vates a G-­‐protein coupled receptor –  G-­‐protein ac4vates Phospholipase C •  Phospholipase C splits a plasma membrane phospholipid to diacylglycerol (DAG) •  Ac4on –  Ac4vates protein kinase C •  Protein kinase C ac4vates other intracellular proteins Inositol Triphosphate (IP3) 2nd messenger •  Source –  1st messenger ac4vates a G-­‐protein coupled receptor –  G-­‐protein ac4vates Phospholipase C •  Phospholipase C splits a plasma membrane phospholipid to inositol triphosphate (IP3) •  Ac4on -  IP3 Binds to ligand gated Ca2+ channels on the smooth ER -  Ligand-­‐gated Ca2+ channels open and increase cytoplasmic [Ca2+] -  Increased calcium levels con4nue the cascade of events leading to the cells response DAG and IP3 2nd messengers Protein Kinase C is ac4vated by DAG and Ca2+ DAG and IP3 2nd messengers Calcium (Ca2+) 2nd messenger •  Source -  In the plasma membrane: -  Ligand gated Ca2+ channels -  Voltage gated Ca2+ channels -  G-­‐protein ac4ves Ca2+ channels -  Ca2+ released from the smooth ER (mediated by IP3 or Ca2+ entering the cytoplasm) -  Ac4ve transport of Ca2+ is inhibited by a 2nd messenger •  Ac4on -  Ca2+ ac4vates calmodulin -  Ac4vates calmodulin-­‐dependent protein kinases -  Ca2+ binds to and alters protein ac4vity directly Calcium (Ca2+) 2nd messenger •  Remember…ac=ve transport systems in the plasma membrane and organelles maintain low cytoplasmic [Ca2+] •  Maintains an electrochemical gradient Arachidonic Acid 2nd messenger •  Source –  1st messenger binds to a g-­‐coupled membrane receptor which ac4vates an enzyme (Phospholipase 2) present in the membrane of the cell –  An enzyme (Phospholipase 2) splits off arachidonic acid from a membrane phospholipid •  Ac4on –  Can be metabolized by two different pathways to produce eicosanoids •  Cyclooxygenase (COX) pathway or lipoxygenase (LOX) pathway •  Eicosanoids may act as 2nd messengers or as local paracrine/
autocrine agents Arachidonic Acid 2nd messenger •  NSAIDS block the COX pathway •  reduce pain, fever, inflamma4on •  Adrenal steroids inhibit phospholipase A2 •  blocks the produc4on of all eicosanoids •  Eicosanoids are produced from arachidonic acid –  Prostaglandins –  Thromboxanes –  Leukotrines Eicosanoids Prostaglandins, Thromboxanes, Leukotrines •  Signaling molecules in CNS –  Hormones –  Paracrine/paracrine agents •
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Some4mes called “super” hormones Derived from Omega-­‐3 and Omega-­‐6 faCy acids Involved in inflamma4on and immunity Very complex control systems v Cor.sol inhibits eicosanoid produc.on Stopping Signal Transduc4on Pathways •  Chronic overs4mula4on in cells can be detrimental •  Presence of 2nd messengers are transient •  Physiological controls to stop receptor ac4va4on 1.  Enzymes in the vicinity metabolize the 1st messenger 2.  Phosphoryla4ng the receptor •  May decrease it’s affinity for the messenger •  May prevent further binding of G-­‐proteins binding to the receptor 3.  Endocytosis of messenger-­‐receptor complex