Cell Communication Chapter 9

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3 Communication between cells requires Ligand – signaling molecule Receptor protein – molecule to which the receptor binds Interaction of these two components initiates the process of signal transduction, which converts the information in the signal into a cellular response

4 Four basic mechanisms for cellular communication 1.Direct contact 2.Paracrine signaling 3.Endocrine signaling 4.Synaptic signaling Some cells send signals to themselves (autocrine signaling) Important in early development

5 Signal transduction Events within the cell that occur in response to a signal When a ligand binds to a receptor protein, the cell has a response Different cell types can respond differently to the same signal –Epinephrine example

6 Phosphorylation Addition of phosphate group A cell’s response to a signal often involves activating or inactivating proteins Phosphorylation is a common way to change the activity of a protein Protein kinase – an enzyme that adds a phosphate to a protein Phosphatase – an enzyme that removes a phosphate from a protein

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8 Receptor Types Receptors can be defined by their location 1.Intracellular receptor – located within the cell 2.Cell surface receptor or membrane receptor 1). located on the plasma membrane to bind a ligand outside the cell 2). Transmembrane protein in contact with both the cytoplasm and the extracellular environment

9 3 subclasses of membrane receptors 1.Chemically gated ion channels – channel-linked receptors that open to let a specific ion pass in response to a ligand Enzymatic receptors – receptor is an enzyme that is activated by the ligand –Almost all are protein kinases 1.G protein-coupled receptor – a G-protein (bound to GTP) assists in transmitting the signal from receptor to enzyme (effector)

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11 Intracellular Receptors Steroid hormones –Common nonpolar, lipid-soluble structure –Can cross the plasma membrane to a steroid receptor –Binding of the hormone to the receptor causes the complex to shift from the cytoplasm to the nucleus –Act as regulators of gene expression

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13 A steroid receptor has 3 functional domains 1.Hormone-binding domain 2.DNA-binding domain 3.Domain that interacts with coactivators to affect level of gene transcription In its inactive state, the receptor typically cannot bind to DNA because an inhibitor protein occupies the DNA binding site Binding of ligand changes conformation

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Coactivators Target cell’s response to a lipid-soluble cell signal can vary enormously, depending on the nature of the cell Even the same type of cell may have different responses Depends on coactivators present Estrogen has different effects in uterine tissue than mammary tissue –Not presence or absence of receptor –Presence or absence of coactivator 15

16 Receptor Kinases Protein kinases phosphorylate proteins to alter protein function Receptor tyrosine kinases (RTK) –Influence cell cycle, cell migration, cell metabolism, and cell proliferation Alteration to function can lead to cancer –Membrane receptor –Plants possess receptors with a similar overall structure and function

RTKs have –A single transmembrane domain Anchors them in membrane –Extracellular ligand-binding domain –Intracellular kinase domain Catalytic site of receptor acts as protein kinase When a ligand binds, dimerization and autophosphorylation occur Cellular response follows – depends on cellular response proteins 17

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Insulin receptor Activated receptor has phosphorylated sites that allow docking Insulin is a hormone that helps to maintain a constant blood glucose level Lowers blood glucose 19

20 Kinase cascade Mitogen-activated protein (MAP) kinases –Important class of cytoplasmic kinases –Mitogens stimulate cell division –Activated by a signaling module called a phosphorylation cascade or kinase cascade –Series of protein kinases that phosphorylate each other in succession –Amplifies the signal because a few signal molecules can elicit a large cell response

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Scaffold proteins Thought to organize the components of a kinase cascade into a single protein complex Binds to each individual kinase such that they are spatially organized for optimal function Benefit in efficiancy Disadvantage in reducing amplification effect 23

24 G-Protein Coupled Receptors G-protein – protein bound to GTP G-protein-coupled receptor (GPCRs) – receptors bound to G proteins  G-protein is a switch turned on by the receptor  G-protein then activates an effector protein (usually an enzyme)

Ras proteins Small GTP-binding protein (G protein) Link between the RTK and the MAP kinase cascade Ras protein is mutated in many human tumors, indicative of its central role in linking growth factor receptors to their cellular response Ras can regulate itself – stimulation by growth factors is short-lived 25

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27 G-Protein Coupled Receptors Single largest category of receptor type in animal cells is GPCRs Receptors act by coupling with a G protein G protein provides link between receptor that receives signal and effector protein that produces cellular response All G proteins are active when bound to GTP and inactive when bound to GDP Effector proteins are usually enzymes

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Often, the effector proteins activated by G proteins produce a second messenger 2 common effectors 1.Adenylyl cyclase –Produces cAMP –cAMP binds to and activates the enzyme protein kinase A (PKA) –PKA adds phosphates to specific proteins 2.Phospholipase C –PIP 2 is acted on by effector protein phospholipase C –Produces IP 3 plus DAG –Both act as second messengers 29

30 Adenylyl cyclase

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Calcium Ca 2+ serves widely as second messenger Intracellular levels normally low Extracellular levels quite high Endoplasmic reticulum has receptor proteins that act as ion channels to release Ca 2+ Most common receptor binds IP 3 32

33 Cell-to-Cell Interactions Cells can identify each other by cell surface markers -Glycolipids are commonly used as tissue-specific markers -Major histocompatibility complex (MHC) proteins are used by cells to distinguish “self” from “nonself” Different receptors can produce the same second messengers Hormones glucagon and epinephrine can both stimulate liver cells to mobilize glucose –Different signals, same effect –Both act by same signal transduction pathway

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Single signaling molecule can have different effects in different cells Existence of multiple forms of the same receptor (subtypes or isoforms) Receptor for epinephrine has 9 isoforms –Encoded by different genes –Sequences are similar but differ in their cytoplasmic domains Different isoforms activate different G proteins leading to different signal transduction pathways 35