Cellular Communication Biology AP Todeschini

Cell Signaling is Nothing New Microbes are a window on the role of cell signaling in the evolution of life Signals and pathways are highly conserved in evolution of life

How Cells Communicate-Signal Transduction 3 phases of Signal Transduction Reception-binding of a ligand(signaling molecule) Transduction- transmission of signal into cell Response- cellular action

How Signals are Sent Local Signals Signals can be sent to nearby cells with or without contact

How Signals are Sent Long Distance Signals Hormone signaling plays an important role in the endocrine and nervous system These signals can be slow but long lasting

1. Reception Figure 11.6 Overview of cell signaling The binding between a signal molecule (ligand) and receptor is highly specific A shape change in a receptor is often the initial transduction of the signal Most signal receptors are plasma membrane proteins

2. Transduction Signal transduction usually involves multiple steps Multistep pathways can amplify a signal: A few molecules can produce a large cellular response Multistep pathways provide more opportunities for coordination and regulation of the cellular response

3. Response Results in change of cellular activities Many signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus

Receptors in the Plasma Membrane There are three main types of membrane receptors: G protein-coupled receptors Receptor tyrosine kinases Ion channel receptors

G protein-coupled receptor A G protein-coupled receptor is a plasma membrane receptor that works with the help of a G protein The G protein acts as an on/off switch: If GDP is bound to the G protein, the G protein is inactive

Ligand binding causes shape change of receptor binds to G Protein Intercellular portion of receptor cannot bind to G protein G protein activates the effector protein. Effector Enzyme tranduces signal to cause cellular response

Receptor tyrosine kinases Kinase is a protein that “phosphorylates” or adds a phosphate to another molecule. Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines residues. They form dimers when a ligand is bound. Remain active as long as the ligand is bound.

In absence of ligand receptors are separate Binding of ligand causes dimerization Kinase portion of receptor adds phospshates Target proteins are activated causing response

ligand-gated ion channel A receptor acts as a gate when the receptor changes shape When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+, through a channel in the receptor

ligand-gated ion channel In absence of ligand gate is closed Ligand binding open the channel Release of ligand allows channel to close

Extracellular vs. Intracellular Receptors

Intracellular Receptors These receptors are not found on the outside of the cell membrane, they are found internally. Their ligands are typically hydrophobic lipid based compounds that can easily cross the cell membrane. Examples of hydrophobic messengers are the steroid and thyroid hormones of animals

Hormone (testosterone) Plasma membrane Receptor protein DNA NUCLEUS Fig. 11-8-1 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-2 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-3 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-4 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor mRNA NUCLEUS CYTOPLASM

Hormone (testosterone) Plasma membrane Receptor protein Hormone- Fig. 11-8-5 Hormone (testosterone) EXTRACELLULAR FLUID Plasma membrane Receptor protein Hormone- receptor complex DNA Figure 11.8 Steroid hormone interacting with an intracellular receptor mRNA NUCLEUS New protein CYTOPLASM

Signal Transduction Pathways Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated Multistep pathways can amplify a signal: A few molecules can produce a large cellular response At each step, the signal is transduced into a different form, usually a shape change in a protein

Protein kinases transfer phosphates from ATP to protein, a process called phosphorylation Protein phosphatases remove the phosphates from proteins, a process called dephosphorylation This phosphorylation and dephosphorylation system acts as a molecular switch, turning activities on and off

Transduction Second Messengers After binding of ligand to receptor there are molecules who will tranduce the signal in the cell, directly causing a cellular response. Second messengers participate in pathways initiated by G protein-coupled receptors and receptor tyrosine kinases

Transduction Second Messengers Cyclic AMP (cAMP) is one of the most widely used second messengers

Transduction Second Messengers Calcium ions (Ca2+) act as a second messenger in many pathways Calcium is an important second messenger because cells can regulate its concentration

Transduction Calcium Ions and Inositol Triphosphate (IP3) Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as additional second messengers The formation of inositol triphosphate (IP3) leads to release of Calcium from the smooth ER

EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein Fig. 11-13-1 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Ca2+ CYTOSOL

EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein Fig. 11-13-2 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Ca2+ Ca2+ (second messenger) CYTOSOL

EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein Fig. 11-13-3 EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein DAG GTP G protein-coupled receptor PIP2 Phospholipase C IP3 (second messenger) IP3-gated calcium channel Figure 11.13 Calcium and IP3 in signaling pathways Endoplasmic reticulum (ER) Various proteins activated Cellular responses Ca2+ Ca2+ (second messenger) CYTOSOL

Overview Multistep pathways have two important benefits: Amplifying the signal (and thus the response) Contributing to the specificity of the response

Amplification One signaling molecule can create many times more secondary signaling creating and maintaining an intense response. Not true for lipid based ligands that must enter the cell and/or nucleus. -Their response is slower but can be long lasting, ex: reproductive hormones(progesterone, testosterone, estrogen)

An Example: Epinepherine(Adrenaline) Released from adrenals during “flight or fight”, sympathetic response of nervous system. The ligand can have very different responses depending on the target cell.

Quorum Sensing in Bacteria Communication among microbes that alters gene expression once a certain population density is achieved. Vibrio Fisheri are a bacteria that live symbiotically within other organisms and produce a glowing protein when their density is high enough. Bacteria can form biofilms using quorum sensing to establish complex, stable ecosystems.

Apoptosis Apoptosis is programmed or controlled cell suicide A cell is chopped and packaged into vesicles that are digested by scavenger cells Apoptosis prevents enzymes from leaking out of a dying cell and damaging neighboring cells

Apoptosis Apoptosis can be triggered by: An extracellular death-signaling ligand DNA damage in the nucleus Protein misfolding in the endoplasmic reticulum Normal part of organisms development

Diabetes The most common medication for type 2 diabetes is Metformin. It is a drug that activates an enzyme in your cells called AMPK. AMPK is the cell signaling pathway that makes the cell activate the GLUT-4 glucose transporter in the cell wall take up glucose for energy. AMPK is normally activated during cardiovascular exercise and it takes up glucose because it needs more for the increase metabolic activity in the muscles.  When an artificial activation of AMPK is initiated by a drug, the cells are slammed with glucose it's not using.