* Signal transduction pathway – the process by which a signal on the cell’s surface is converted into a specific cellular response * Cell to cell signaling first evolved in ancient prokaryotes.

Exchange of mating factors Receptor  factor a factor Yeast cell, mating type a Yeast cell, mating type  Mating New a/  cell a a a/   

* Local regulators – a substance that influences cells in the vicinity * Examples of local regulators are growth factors * Growth factors stimulate nearby cells to grow and multiply * Many cells can respond to signals from a single cell in their vicinity – paracrine signaling * Neurotransmitters are signals sent from one nerve cell to single adjacent nerve cell.

* Both plants and animals use hormones for signaling a great distances. * This is known as endocrine signaling * Signaling cells release hormones into the blood vessels and they travel to target cells in other parts of the body. * In plants, hormones can travel in vessels, but also move through cells and by diffusion as a gas

* Hormones come in all shapes and molecular structures * Ex. Ethylene in plants is formed from a hydrocarbon of only six atoms * Insulin in humans is a protein composed of thousands of atoms

Local signaling Long-distance signaling Target cell Secreting cell Secretory vesicle Local regulator diffuses through extracellular fluid. (a) Paracrine signaling(b) Synaptic signaling Electrical signal along nerve cell triggers release of neurotransmitter. Neurotransmitter diffuses across synapse. Target cell is stimulated. Endocrine cell Blood vessel Hormone travels in bloodstream. Target cell specifically binds hormone. (c) Endocrine (hormonal) signaling

* Cells can also communicate through direct contact through cell junctions and cell recognition

Plasma membranes Gap junctions between animal cells Plasmodesmata between plant cells (a) Cell junctions (b) Cell-cell recognition

1. Reception – when the target cell detects the signal – signal binds to receptor protein in membrane 2. Transduction – signal changes the protein, most often resulting in a cascade of rxns. In the cell. 3. Response – the cascade of rxns. Triggers a cell response – this could be an enzyme catalyzed reaction, structural rearrangement, activation of specific genes

Plasma membrane EXTRACELLULAR FLUID CYTOPLASM ReceptionTransduction Response Receptor Signaling molecule Activation of cellular response Relay molecules in a signal transduction pathway 3 2 1

* A signal molecule adheres to a target cell as a result of ligand binding * Ligands are small molecules that adhere to larger ones. * When the ligand binds, the receptor protein changes shape or aggregates with other receptors * Most receptor proteins are located in the plasma membrane

1. G-protein-linked receptors 2. Tyrosine-kinase receptors 3. Ion-channel receptors 4. Intracellular receptors

* These are plasma membrane receptors that works with a G protein * Yeast mating factors, epinephrine, neurotransmitters and hormones use these receptors * They have 7 alpha helices spanning the membrane * The G protein in loosely attached to the cytoplasmic side of the membrane and functions as an on/off switch for the receptor * When GDP is bound, the G protein is inactive * When GTP is bound, the G protein is active

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* G-protein linked receptors are essential for embryonic development and sensory reception * Bacteria that cause whooping cough and cholera infect by interfering with G-protein receptors

* These are often the receptor for growth factor * They have a single alpha helix spanning the membrane * The area on the cytoplasmic side of the membrane is an enzyme called tyrosine kinase.

1. When signal molecules attach to binding sites, the two polypeptides unite and form a dimer 2. Using phosphates from ATP, the dimer is phosphorylated 3. These phosphorylated tyrosine regions then attach relay proteins 4. These can start several transduction pathways Ex. Growth factors are examples

* Ligand-gated * Proteins that act as pores that allow (or block) ion passage in and out of the membrane * Na + and Ca 2+ * Nerve cells are examples * Ch. 48

* In a mammalian neuron at resting potential, the concentration of K + is highest inside the cell, while the concentration of Na + is highest outside the cell * Sodium-potassium pumps use the energy of ATP to maintain these K + and Na + gradients across the plasma membrane * These concentration gradients represent chemical potential energy * In a resting neuron, the currents of K + and Na + are equal and opposite, and the resting potential across the membrane remains steady

* An action potential can be considered as a series of stages * At resting potential 1. Most voltage-gated sodium (Na + ) channels are closed; most of the voltage-gated potassium (K + ) channels are also closed * When an action potential is generated 2. Voltage-gated Na + channels open first and Na + flows into the cell 3. During the rising phase, the threshold is crossed, and the membrane potential increases 4. During the falling phase, voltage-gated Na + channels become inactivated; voltage-gated K + channels open, and K + flows out of the cell 5. During the undershoot, membrane permeability to K + is at first higher than at rest, then voltage-gated K + channels close and resting potential is restored

OUTSIDE OF CELL INSIDE OF CELL Inactivation loop Sodium channel Potassium channel Action potential Threshold Resting potential Time Membrane potential (mV)  50  100  50 0 Na  KK Key Resting state Undershoot Depolarization Rising phase of the action potential Falling phase of the action potential

KK KK KK KK Na  Action potential Axon Plasma membrane Cytosol Action potential 2 1 3

© 2011 Pearson Education, Inc. Animation: Synapse Right-click slide / select “Play”

* At electrical synapses, the electrical current flows from one neuron to another * At chemical synapses, a chemical neurotransmitter carries information across the gap junction * Most synapses are chemical synapses

* The presynaptic neuron synthesizes and packages the neurotransmitter in synaptic vesicles located in the synaptic terminal * The action potential causes the release of the neurotransmitter * The neurotransmitter diffuses across the synaptic cleft and is received by the postsynaptic cell

Presynaptic cell Postsynaptic cell Axon Presynaptic membrane Synaptic vesicle containing neurotransmitter Postsynaptic membrane Synaptic cleft Voltage-gated Ca 2  channel Ligand-gated ion channels Ca 2  Na  KK

* Proteins dissolved in the cytosol or in the nucleus * Signal molecules must be able to pass through the phospholipid bilayer * Steriod hormones – testosterone – pg. 205 * An activated hormone-receptor complex can act as a transcription factor, turning on specific genes

Hormone (testosterone) Receptor protein Plasma membrane EXTRACELLULAR FLUID Hormone- receptor complex DNA mRNA NUCLEUS CYTOPLASM New protein

© 2011 Pearson Education, Inc. Animation: Lipid-Soluble Hormone Right-click slide / select”Play”

* Protein phosphorylation using protein kinases * Protein kinases phosphorylate their substrates on serine or threonine amino acids * Phosophorylation causes a shape change rendering a protein active or inactive * 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 or up or down, as required

Receptor Signaling molecule Activated relay molecule Phosphorylation cascade Inactive protein kinase 1 Active protein kinase 1 Active protein kinase 2 Active protein kinase 3 Inactive protein kinase 2 Inactive protein kinase 3 Inactive protein Active protein Cellular response ATP ADP ATP ADP ATP ADP PP P P P P i

* The ligand is a pathway’s “first messenger” * Second messengers are small, nonprotein, water-soluble molecules or ions that spread throughout a cell by diffusion * Second messengers participate in pathways initiated by G protein linked receptors and tyrosine-kinase receptors

Cyclic AMP (cAMP) is one of the most widely used second messengers Adenylyl cyclase, an enzyme in the plasma membrane, converts ATP to cAMP in response to an extracellular signal * Many signal molecules trigger formation of cAMP * cAMP usually activates protein kinase A, which phosphorylates various other proteins * In the absence of a hormone – phosphdiesterase converts cAMP to AMP

G protein First messenger (signaling molecule such as epinephrine) G protein-coupled receptor Adenylyl cyclase Second messenger Cellular responses Protein kinase A GTP ATP cAMP

© 2011 Pearson Education, Inc. Animation: Signal Transduction Pathways Right-click slide / select “Play”

* Calcium ions (Ca 2+ ) act as a second messenger in many pathways * Used in muscle contraction, cell division, and cell secretion * Ca 2+ is used in GPCR and RTK * Pathways leading to the release of calcium involve inositol triphosphate (IP 3 ) and diacylglycerol (DAG) as additional second messengers

Mitochondrion EXTRACELLULAR FLUID Plasma membrane Ca 2  pump Nucleus CYTOSOL Ca 2  pump Endoplasmic reticulum (ER) ATP Low [Ca 2  ] High [Ca 2  ] Key

G protein EXTRA- CELLULAR FLUID Signaling molecule (first messenger) G protein-coupled receptor Phospholipase C DAG PIP 2 IP 3 (second messenger) IP 3 -gated calcium channel Endoplasmic reticulum (ER) CYTOSOL Various proteins activated Cellular responses Ca 2  (second messenger) Ca 2  GTP

Reception Transduction Response Binding of epinephrine to G protein-coupled receptor (1 molecule) Inactive G protein Active G protein (10 2 molecules) Inactive adenylyl cyclase Active adenylyl cyclase (10 2 ) ATP Cyclic AMP (10 4 ) Inactive protein kinase A Active protein kinase A (10 4 ) Inactive phosphorylase kinase Active phosphorylase kinase (10 5 ) Inactive glycogen phosphorylase Active glycogen phosphorylase (10 6 ) Glycogen Glucose 1-phosphate (10 8 molecules)

* Heart and liver cells respond to epinephrine binding in different ways * Liver breaks down glycogen/heart starts beating faster * Scaffolding proteins – large relay proteins responsible for activating large kinase complexes

Signaling molecule Receptor Plasma membrane Scaffolding protein Three different protein kinases

* Bacteria that colonize the lining of the small intestine * Produce a toxin that modifies the shape of the G protein responsible for salt and water secretion * G protein is unable to hydrolyze GTP to GDP * G-protein is stuck in ACTIVE state * More cAMP is made * Cells continue to secrete large amounts of water into intestines * Profuse diarrhea