CHAPTER 11: CELL COMMUNICATION

Cell communication is essential for multicellular organisms:Zygote Embryo Fetus Baby Adult

= ensures that crucial activities occur in the correct cells, at the right time, and in proper coordination with the other cells of the organism

Signals received can be from internal, other cells, or the environment (light, touch, etc)However they most often are “chemical” signals

Unicellular Yeast“Conversation” of sex-2 sexes-a and α-Secrete “factors”

Signal – Transduction Pathway = signal on surface is transferredinto a response

Evolved in Prokaryotes Eukaryotes

Communicating cells may be close together or far apart

Paracrine Signaling:= local signaling (animals) where numerous cells can simultaneously receive/respond to molecules produced by a single cell

Local Regulator = substance that influences cells in the vicinity

Synaptic Signaling:= single target cell (neurons)

Electrical impulse triggers secretion of neurotransmitter

Hormone = chemical used for greater distances (plants and animals)

Plants = air borneEthylene (C2H4) – ripening of fruit and regulate growth

Hormonal Signaling:= long distance

Communicate by direct contact

= connect cytoplasm of adjacent cells

Dissolved in cytosol and pass “freely” from one cell to another

Surface molecules

Signal “transduced” into cell triggers response

3 Stages of Cell Signaling Earl Sutherland (1971) = Noble Prize“How epinephrine stimulates breakdown of glycogen glucose in liver cells and skeletal muscle cellsAKA “Adrenaline”Function of epinephrine = mobilization of fuel reserves during times of physical and mental stress

1. Reception = the target cell’s detection of a signal coming from outside the cellChemical signal is “detected” when it binds to a cellular protein, usually at cell surface

2. Transduction = the binding of the signal molecule changes the receptor protein in some way, initiating the process of transductionTransduction converts the signal to a form that can bring about a specific cellular responseMost of the time it occurs in a sequence of changes in a series of different molecules – a signal transduction “pathway”The molecules of the pathway are often called “relay” molecules

3. Response = the transduced signal triggers a specific cellular response A variance of responses: catalysis of an enzyme, rearrangement of cytoskeleton, activation of a specific gene

- A target cell’s receptor proteins “recognize” the signal molecule-The signal molecule is complementary in shape to a specific site on the receptor and attaches “Lock-and-Key”-Ligand = a small molecule that specifically binds to a larger one-Ligand binding generally causes a receptor protein to undergo a change in conformation (shape)-This directly activates the receptor so that it can interact with another cellular molecule

1. Signal Reception and Initiation of Transduction

- Most signal molecules are water soluble and too large to pass PM- Most of these bind to specific sites on receptor proteins embedded in PM-Such a receptor transmits info from the ECM to the inside of the cell by changing shape or aggregating

Epinephrine

3 Major Types of Membrane Receptors:1.G-Protein-Linked Receptors2.Tyrosine-Kinase Receptors3.Ion Channel Receptors

G-Protein-Linked Receptors =a PM receptor that works with the help of a G-protein

7 alpha-helices spanning the membraneLoosely attached to cytoplasm side G protein:

Function as a switch that is on or off depending on Guanine Nucleotides-GDP = inactive-GTP = active

ATP GTP Guanine

Steps in Activation:1. Signal protein binds and activates the G-protein-linked receptor causing a conformational change

This in turn causes the binding of a inactive G protein2. A molecule of GTP displaces the GDP of the G protein3. This activates the G protein, which then (moving freely along the PM) binds to and activates the enzyme4. This triggers the next step in the pathway leading to a response

-The G protein catalyzes the hydrolysis of its GTP (functions as GTPase) and dissociates from the enzyme, becoming available for reuse- All 3 proteins remain attached to the PM- When the signal molecule isn’t present, the pathway shuts down

G protein receptors are widespread and diverse in functions:-Embryonic development-Vision and Smell-Involved in human diseases caused by bacteria (toxins that interfere with G protein functions)

Cholera, Pertussis (Whooping Cough), Botulism-60% of all drugs used today to treat infections and diseases exert their effects on G protein pathways

Tyrosine-Kinase Receptors- Work with growth factors involved in cell growth/ reproduction, protein synthesis, chromosome duplication, and

cytoskeleton configuration- Have enzymatic activity- Specialization for triggering more than one signal-transduction pathway at once

Tyrosine-Kinase = the part of the receptor protein functioning as the enzyme (on cytoplasmic side) = catalyzes the transfer of phosphate groups from ATP to the amino acid Tyrosine on a substrate proteinTyrosine-Kinase Receptors = membrane receptors that attach phosphates to protein tyrosines

The receptors exist as two separate polypeptides before the signal molecules bindsEach has an extracellular signal-binding site, a single α helix spanning the membrane, and an intracellular tail containing a number of tyrosines

Kinase = an enzyme involved in transferring phosphate groups from ATP to another molecule (phosphorylation)

Growth Factor

Activation occurs in 2 steps:1.The ligand binding causes 2 receptor polypeptides to aggregate, forming a dimer ( a protein consisting of 2 polypeptides)2.The aggregation activates the tyrosine-kinase parts of both polypeptides, each of which then adds phosphates to the tyrosines

3. Now that the receptor protein is fully activated, it is recognized by specific relay proteins inside the cell. Each such protein binds to a specific phosphorylated tyrosine, undergoing a structural change that activates it4. One tyrosine-kinase receptor dimer may activate 10 or more different intracellular proteins simultaneously, triggering as many different transduction pathways and cellular responses

Key difference between tyrosine-kinase receptors and G-protein-linked receptors: the ability of a single ligand-binding event to trigger so many pathwaysAbnormal tyrosine-kinase receptors that aggregate even without ligand cause some kinds of cancers

Ion-Channel Receptors= protein pores in the PM that open or close in response to a chemical signal, allowing or blocking the flow of specific ions, such as Na+ or Ca2+

- These proteins bind a signal molecule as a ligand at a specific site on their extracellular side- The shape change produced in the channel protein immediately leads to a change produced in the concentration of a particular ion inside the cell- Change in ion concentration triggers cellular responses- At a synapse between nerve cells it may trigger an electrical signal that propagates down the length of the receiving cell- Ligand-gated ion channels are very important in the nervous system as are gated channels

Intracellular Receptors

- Signal receptors in the cytosol or nucleus of target cells- Chemical messengers must be able to diffuse into cells - Hydrophobic to cross the phospholipid interior- Steroids and Thyroid hormones of animals

Testosterone (steroid hormone)- Secreted by cells of the testes- Travels through the blood and enters cells-Target cells have intracellular receptors which bind with testosterone, activating it-With the hormone attached, the active form of the receptor protein then enters the nucleus and turns on specific genes that controls male sex characteristics-The gene is transcribed into mRNA then translated into a protein-Special proteins called “transcription factors” control which genes are turned on in a particular cell at a particular time-The activated testosterone receptor is a transcription factor that regulates specific genes-By acting as a transcription factor, the testosterone receptor itself carries out the complete transduction of the signal-Estrogen receptors are already in the nucleus when estrogen reaches them-Many of these intracellular receptor proteins are structurally similar, suggesting evolutionary kinship

2. Signal-Transduction PathwaysWhen signal receptors are PM proteins, the transduction stage is usually a multistep pathway

Relay Molecules

Protein interaction is a unifying theme of all regulation at the cellular level

The original signal molecules isn’t “physically passed” alongSignal is “transduced” into a different form (conformational change commonly brought about by phosphorylation)

Activate a protein by adding one or more phosphate groups Conformational Change

Protein Kinase = an enzyme that transfers phosphate groups from ATP to a protein (usually serine or threonine charged/polar amino acids)

Sequence is similar in yeast mating and animal growth factors

Inactive Active

1% of our genes code for P-K’s (important?)

Regulate a large proportion of cellular proteins (like cell reproduction)

Abnormal activity Cancer

Protein Phosphatases = Enzymes that remove phosphate groups from proteins

Regulate by turning “off” the pathway

Regulation depends on the balance between active kinase and phosphatases

When signal isn’t present, phosphatase dominate = signal shut down

Certain Small Molecules and Ions are Key Components of Signaling Pathways

Not all components of signal-transduction pathways are proteinsSecond Messengers = non protein, water soluble molecules or ions involved in signaling pathways

Readily spread throughout the cell by diffusion (small and water soluble)

Participate in pathways initiated by both G-protein-linked receptors and Tyrosine-Kinase receptors

The two most widely used second messengers are cyclic AMP and calcium ions (Ca2+)

Cyclic AMP (cAMP)

Once Sutherland had established that epinephrine causes glycogen breakdown without entering the cell, the search began for “second messengers”

Sutherland found that the binding of epinephrine to the PM of a liver cell elevates cystosolic concentrations of cyclic AMP or cAMP

Cyclic AMP carries the signal initiated by epinephrine from the PM of liver/muscle cells into the cell interior Response (Glycogen to Glucose)

Adenylyl Cyclase = an enzyme built into the PM that converts ATP to cAMP in response to a extracellular signal (like epinephrine)

Adenylyl Cyclase only becomes active after the signal molecule (epinephrine) binds to a specific receptor protein

The first messenger (hormone) causes a membrane enzyme to make cAMP, which broadcasts the signal to the cytoplasm

The cAMP doesn’t persist for long in the absence of the hormone, because another enzyme converts the cAMP to an inactive product (AMP)

G proteins, G-protein-linked receptors, and protein kinases

The immediate effect of cAMP is usually the activation of a serine/threonine kinase called Protein Kinase A

The activated kinase then phosphorylates various other proteins depending on the cell

G-protein-linked receptor

Cholera:Bacterium, Vibrio choleraeContaminated waterColonize the lining of the small intestine Produce a toxin (enzyme)Enzyme chemically modifies a G protein involved in regulating salt and water secretionBecause the modified G protein is unable to hydrolyze GTP to GDP, it remains stuck in its active formThis continuously stimulates adenylyl cyclase to make cAMPThe high concentration of cAMP cause the intestinal cells to secrete large amounts of water and salts into the intestinesProfuse diarrhea Could lead to death (dehydration and loss of salts)

Calcium ions and Inositol Triphosphate

Many signal molecules in animals, including neurotransmitters, growth factors, and some hormones, induce responses in their target cells via signal-transduction pathways that increase the cytosolic concentrations o f calcium ions

Calcium is even more widely used than cAMP as a second messenger

Animals: muscle cell contractions, secretion of certain substances, and cell divisionPlants: coping with environmental stresses (drought and cold)

Function in both G-protein and Tyrosine-Kinase pathways

Calcium ions concentration is lower in the cytosol than ECF (1000 times lower)Actively transported from cytosol to: ECF, Endoplasmic Reticulum, Mitochondria/Chloroplast = maintains low cytosolic concentrationsCalcium ion PumpsThe low concentration allows Ca2+ to be used as a second messenger

In response to a signal relayed by a signal-transduction pathway, the cytosolic calcium level may rise

The pathways leading to calcium release involve still other second messengers: diacylglycerol (DAG) and inositol trisphosphate (IP3)

These two messengers are produced by cleavage of a certain kind of phospholipid in the PM

IP3 stimulates the release of calcium from the ERCalcium as a “third messenger”

Calcium ion binding proteinConformation change and then binds to other proteins (protein kinases and phosphatases)

3. Cellular Responses

Regulation of gene activity

Phosphorylation Cascade

ATP not shown

Transcription Factor = a gene regulating protein

Transcription andTranslation Protein

When signal receptors are PM proteins, the transduction stage is usually a multistep pathwayThe benefit is the possibility of greatly amplifying the signal