Molecular Biology of the Cell Alberts • Johnson • Lewis • Raff • Roberts • Walter Molecular Biology of the Cell Fifth Edition Chapter 15 Mechanisms of Cell Communication Copyright © Garland Science 2008

Communication between cells is mediated by extracellular signals Figure 15-1 Molecular Biology of the Cell (© Garland Science 2008)

Cells respond to the extracellular environment: example: Saccharomyces cerevisiae Figure 15-2 Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-3a Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-3b Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-4 Molecular Biology of the Cell (© Garland Science 2008)

- Act at very low concentration Endocrine signaling : - slow - Act at very low concentration Figure 15-5a Molecular Biology of the Cell (© Garland Science 2008)

- High local concentration Synaptic signaling - Fast and precise - High local concentration Figure 15-5b Molecular Biology of the Cell (© Garland Science 2008)

Extracellular signal can act slow or rapidly to change the behavior of a target cell Figure 15-6 Molecular Biology of the Cell (© Garland Science 2008)

Gap junctions allow neighboring cells to share signaling information Allow small molecules to pass freely between cells, like Calcium, Cyclic AMP (2nd messenger) Figure 15-7 Molecular Biology of the Cell (© Garland Science 2008)

Cells are programmed to respond to specific combinations of extracellular signal molecules Figure 15-8 Molecular Biology of the Cell (© Garland Science 2008)

Different types of cells usually respond differently to the same extracellular signal molecules Figure 15-9 Molecular Biology of the Cell (© Garland Science 2008)

The fate of some developing cells depends on their position in Morphogen gradients Figure 15-10 Molecular Biology of the Cell (© Garland Science 2008)

The cell can alter the concentration of an intracellular molecule quickly if the lifetime of the molecule is short Figure 15-11 Molecular Biology of the Cell (© Garland Science 2008)

Nitric oxide acts as a signaling molecule, it relaxes smooth muscles Nitroglycerides used on patients with angina – reduces the work load of the heart. Figure 15-12b Molecular Biology of the Cell (© Garland Science 2008)

These bind to intracellular receptors to regulate gene expression Small hydrophobic molecules that diffuse directly across the plasma membrane These bind to intracellular receptors to regulate gene expression Figure 15-13 Molecular Biology of the Cell (© Garland Science 2008)

THE NUCLEAR RECEPTORS SUPERFAMILY Steroid hormones (cortisol) made of cholesterol, cortisol is made in the adrenal cortex, influences metabolism. Steroid sex hormones made by testes and ovaries – reponsible for secondary sex characteristics Vitamin D – made in the skin, regulates calcium metabolism. * The nuclear receptor (with ligand) then binds to DNA to regulate transcription Figure 15-14a Molecular Biology of the Cell (© Garland Science 2008)

Ligand binding alters the conformation of the receptor Figure 15-14b Molecular Biology of the Cell (© Garland Science 2008)

* In some cases ligand binding inhibits transcription Ligand binding alters the conformation of the receptor: inhibitor dissociates and coactivator binds * In some cases ligand binding inhibits transcription Figure 15-14c Molecular Biology of the Cell (© Garland Science 2008)

The transcription response takes place in multiple steps: primary and secondary responses Figure 15-15 Molecular Biology of the Cell (© Garland Science 2008)

THE THREE LARGEST CLASS OF CELL-SURFACE RECEPTORS Most extracellular signals do not enter the cell like the hydrophobic ones, but they bind to specific receptors at the plasma membrane Ion-channel-coupled G-protein-coupled Enzyme-coupled These receptors act as signal transducers

Mediated by neurotransmitters that open / close the channel Involved in rapid synaptic signaling between nerve cells, and nerve and muscle cells Mediated by neurotransmitters that open / close the channel Most belong to a family of multipass transmembrane proteins Figure 15-16a Molecular Biology of the Cell (© Garland Science 2008)

All belong to a family of multipass transmembrane proteins A trimeric G protein (GTP binding) mediates the interaction between the activated receptor and this target protein. All belong to a family of multipass transmembrane proteins Figure 15-16b Molecular Biology of the Cell (© Garland Science 2008)

Function as enzymes or associate with enzymes that they activate. Are usually single pass transmembrane proteins, ligand binding site outside the cell and catalytic (enzyme-binding) site inside the cell. Majority are protein kinases or associate with protein kinases. Figure 15-16c Molecular Biology of the Cell (© Garland Science 2008)

Most activated cell-surface receptors relay signals via small molecules and a network of intracellular signaling proteins: called second messengers Examples of small messengers: In cytosol: Cyclic AMP : cAMP Calcium ion Fat soluble: Diacylglycerol Large intracellular signaling proteins Figure 15-17 Molecular Biology of the Cell (© Garland Science 2008)

Many intracellular signaling proteins function as switches that are activated by phosphorylation or GTP binding Ser/thre kinases are majority Tyrosine kinases Figure 15-18 Molecular Biology of the Cell (© Garland Science 2008)

Small monomeric GTPases regulated by GTP/GDP binding Figure 15-19 Molecular Biology of the Cell (© Garland Science 2008)

Signal integration: two pathways cause phosphorylation of one target at different sites Figure 15-20 Molecular Biology of the Cell (© Garland Science 2008)

TYPES OF INTRACELLULAR SIGNALING COMPLEXES The scaffold holds signaling proteins in close proximity, the components can interact at high local concentration and be sequentially activated, efficiently and selectively Figure 15-21a Molecular Biology of the Cell (© Garland Science 2008)

TYPES OF INTRACELLULAR SIGNALING COMPLEXES Transient assembly of complexes, due to phosphorylation (that is reversible) Figure 15-21b Molecular Biology of the Cell (© Garland Science 2008)

TYPES OF INTRACELLULAR SIGNALING COMPLEXES Receptor activation leads to the production of modified phospholipids (phosphinositides), which recruit specific intracellular signaling proteins. Figure 15-21c Molecular Biology of the Cell (© Garland Science 2008)

Induced proximity via interaction domains, used to relay signals from protein to protein Figure 15-22 Molecular Biology of the Cell (© Garland Science 2008)

When a cell responds to extracellular signals, it can be a smooth graded or a switch like response Figure 15-23 Molecular Biology of the Cell (© Garland Science 2008)

Looking at a whole population, the response may appear smooth while each cell is having an all or non response It is important to look at individual cells to detect all-or-none responses Figure 15-24b, c Molecular Biology of the Cell (© Garland Science 2008)

Example: Adrenaline binding to a G-protein-coupled cell-surface receptor increases the intracellular concentration of cyclic AMP which in turn activates enzymes that promote glycogen breakdown and inhibit enzymes that promote glycogen synthesis. Figure 15-25 Molecular Biology of the Cell (© Garland Science 2008)

Intracellular signaling incorporate feedback loops Figure 15-26 Molecular Biology of the Cell (© Garland Science 2008)

Positive feedback mechanism giving switch-like behavior Figure 15-27 Molecular Biology of the Cell (© Garland Science 2008)

Positive feedback mechanism depends on the intensity of the stimulus, that results in a signal that persists Negative feedback mechanism counteracts the effect of a stimulus making the system less sensitive Figure 15-28 Molecular Biology of the Cell (© Garland Science 2008)

Target cells can become adapted (desensitized) to an extracellular signal molecule Figure 15-29 Molecular Biology of the Cell (© Garland Science 2008)

More than 700 GPCRs in humans G-protein coupled receptors, the largest class of cell surface receptors More than 700 GPCRs in humans Sigh, smell and taste use these receptors One signal can activate many GPCRs Figure 15-30 Molecular Biology of the Cell (© Garland Science 2008)

Trimeric G-proteins relay signals from GPCRs Various types of G-proteins, each one specific for a particular set of GPCRs, and particular set of target proteins in the membrane They all have similar structures and operate similarly. Gproteins have three subunits: alpha, beta and gamma. Alpha-GDP unstimulated Alpha-GTP stimulated (has intrinsic GTPase); also regulators of G-protein signaling act as GTPases Figure 15-32 Molecular Biology of the Cell (© Garland Science 2008)

Some G-proteins regulate the production of Cyclic AMP Cyclic AMP acts as a second messenger Figure 15-33 Molecular Biology of the Cell (© Garland Science 2008)

Cyclic AMP is synthesized from ATP by a plasma membrane bound enzyme adenylyl cyclase and is quickly destroyed by cAMP phosphodiesterase Different G-proteins cause different effect of cAMP: Stimulatory G-protein (Gs) activates adenylyl cyclase Inhibitory G-protein (Gi) inhibits adenylyl cyclase Ex: cholera toxin is an enzyme that catalyzes transfer of ADP ribose from NAD+ to Gs. Now Gs can no longer hydrolyze the GTP and is always ON, making adenylyl cyclase active always, more cAMP causes more Cl- to be in the gut (and hence more water) Figure 15-34 Molecular Biology of the Cell (© Garland Science 2008)

Individuals with genetic defects in Gs alpha show decrease response to some hormones (so they have metabolic abnormalities, abnormal bone development and are mentally retarded). Table 15-1 Molecular Biology of the Cell (© Garland Science 2008)

Cyclic AMP dependent protein kinase (PKA) mediates most of the effects of cyclic AMP PKA is a Ser/Thre Kinase Figure 15-35 Molecular Biology of the Cell (© Garland Science 2008)

A rise in cyclic AMP can alter gene transcription Figure 15-36 Molecular Biology of the Cell (© Garland Science 2008)

Many GPCRs exert their effects mainly via G proteins that activate the plasma membrane - bound enzyme phospholipase C-b (PLCb) Table 15-2 Molecular Biology of the Cell (© Garland Science 2008)

Phospholipase C-b (PLCb) works on PIP2 to make DAG and IP3 Figure 15-38 Molecular Biology of the Cell (© Garland Science 2008)

IP3 diffuses in the cytoplasm and binds to the ER causing Calcium release in the cytosol Figure 15-39 Molecular Biology of the Cell (© Garland Science 2008)

Calcium functions as an intracellular mediator, for example during fertilization it initiates embryonic development Figure 15-40 Molecular Biology of the Cell (© Garland Science 2008)

In a resting cell, several mechanisms ensure that calcium concentration remains low Figure 15-41a Molecular Biology of the Cell (© Garland Science 2008)

In a resting cell, several mechanisms ensure that calcium concentration remains low Figure 15-41b Molecular Biology of the Cell (© Garland Science 2008)

Various Ca2+-binding proteins help to relay the cytosolic Ca2+ signal: Calmodulin, when bound to Calcium changes conformation Figure 15-43 Molecular Biology of the Cell (© Garland Science 2008)

Activated Calmodulin binds and activates other proteins: CAM Kinase Figure 15-44 Molecular Biology of the Cell (© Garland Science 2008)

Table 15-3 Molecular Biology of the Cell (© Garland Science 2008)

GPCR Kinases and arrestins in GPCR desesitization Figure 15-51 Molecular Biology of the Cell (© Garland Science 2008)

Receptor Tyrosine kinases Figure 15-52 Molecular Biology of the Cell (© Garland Science 2008)

Table 15-4 Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-53a Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-53b Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-54 Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-55a Molecular Biology of the Cell (© Garland Science 2008)

Table 15-5 Molecular Biology of the Cell (© Garland Science 2008)

Figure 15-66 Molecular Biology of the Cell (© Garland Science 2008)