The Cellular Internet
• Cell-to-cell communication is essential for multicellular organisms
• Biologists have discovered some universal mechanisms of cellular regulation
Exchange ofmating factors
Mating
Receptor
a
factor
a
a factorYeast cell,mating type a
Yeast cell,mating type
a/
New a/ cell
Local and Long-Distance Signaling
• Cells in a multicellular organisms communicate by chemical messengers
• Animal and plant cells have cell junctions that directly connect the cytoplasm of adjacent cells
• In local signaling, animal cells may communicate by direct contact
• In many other cases, animal cells communicate using local regulators, messenger molecules that travel only short distances
• In long-distance signaling, plants and animals use chemicals called hormones
Plasma membranes
Gap junctionsbetween animal cells
Cell junctions
Cell-cell recognition
Plasmodesmatabetween plant cells
Paracrine signaling
Local regulatordiffuses throughextracellular fluid
Secretoryvesicle
Secretingcell
Target cell
Local signaling
Electrical signalalong nerve celltriggers release ofneurotransmitter
Neurotransmitter diffuses across synapse
Endocrine cell Bloodvessel
Long-distance signaling
Hormone travelsin bloodstreamto target cells
Synaptic signaling
Target cellis stimulated
Hormonal signaling
Target cell
The Three Stages of Cell Signaling: A Preview
• Earl W. Sutherland discovered how the hormone epinephrine acts on cells
• Sutherland suggested that cells receiving signals went through 3 processes:
– Reception
– Transduction
– Response
EXTRACELLULARFLUID
Reception
Plasma membrane
Transduction
CYTOPLASM
Receptor
Signalmolecule
Relay molecules in a signal transductionpathway
Response
Activationof cellularresponse
Reception: A signal molecule binds to a receptor protein, causing it to change shape
• The binding between a signal molecule (ligand) and receptor is highly specific
• A conformational change in a receptor is often the initial transduction of the signal
• Most signal receptors are plasma membrane proteins
Intracellular Receptors
• Some receptor proteins are intracellular, found in the cytosol or nucleus of target cells
• Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors
• Examples of hydrophobic messengers are the steroid and thyroid hormones of animals
• An activated hormone-receptor complex can act as a transcription factor, turning on specific genes
EXTRACELLULARFLUID
Plasmamembrane
The steroidhormone testosteronepasses through theplasma membrane.
Testosterone bindsto a receptor proteinin the cytoplasm,activating it.
The hormone-receptor complexenters the nucleusand binds to specificgenes.
The bound proteinstimulates thetranscription ofthe gene into mRNA.
The mRNA istranslated into aspecific protein.
CYTOPLASM
NUCLEUS
DNA
Hormone(testosterone)
Receptorprotein
Hormone-receptorcomplex
mRNA
New protein
Receptors in the Plasma Membrane• Most water-soluble signal molecules bind to
specific sites on receptor proteins in the plasma membrane
• There are three main types of membrane receptors:
– G-protein-linked receptors
– Receptor tyrosine kinases
– Ion channel receptors
• A G-protein-linked 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
Segment thatinteracts withG proteins
Signal-binding site
G-protein-linked receptor
• Receptor tyrosine kinases are membrane receptors that attach phosphates to tyrosines
• A receptor tyrosine kinase can trigger multiple signal transduction pathways at once
• A kinase, alternatively known as a phosphotransferase, is a type of enzyme that transfers phosphate groups from high-energy donor molecules, such as ATP, to specific substrates. The process is referred to as phosphorylation.
Signalmolecule
Helix in themembrane
Signal-binding site
Tyr
Tyr
Tyr Tyr
Tyr
TyrTyrosines
Receptor tyrosinekinase proteins(inactive monomers)CYTOPLASM
Tyr
Tyr
Tyr Tyr
Tyr
Tyr Tyr
Tyr
Tyr Tyr
Tyr
Tyr
Tyr
Tyr
Tyr Tyr
Tyr
Tyr
Activated tyrosine-kinase regions(unphosphorylateddimer)
Signalmolecule
Dimer
Fully activated receptor tyrosine-kinase(phosphorylateddimer)
Tyr
Tyr
Tyr Tyr
Tyr
TyrPPP
PPPATP 6 ADP
Tyr
Tyr
Tyr Tyr
Tyr
TyrP
PP
PPP
Inactiverelay proteins
Cellularresponse 2
Cellularresponse 1
Activated relay proteins
6
• An ion channel 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
Signalmolecule(ligand)
Gateclosed Ions
Ligand-gatedion channel receptor
Plasmamembrane
Gate closed
Gate open
Cellularresponse
Transduction: Cascades of molecular interactions relay signals from receptors to target molecules in the cell
• 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
Signal Transduction Pathways
• The molecules that relay a signal from receptor to response are mostly proteins
• Like falling dominoes, the receptor activates another protein, which activates another, and so on, until the protein producing the response is activated
• At each step, the signal is transduced into a different form, usually a conformational change
Protein Phosphorylation and Dephosphorylation
• In many pathways, the signal is transmitted by a cascade of protein phosphorylations
• Phosphatase enzymes remove the phosphates
• This phosphorylation (kinases) and dephosphorylation (phosphatases) system acts as a molecular switch, turning activities on and off
Signal molecule
Activated relaymolecule
Receptor
Inactiveprotein kinase
1 Activeprotein kinase
1
Inactiveprotein kinase
2 Activeprotein kinase
2
Inactiveprotein kinase
3 Activeprotein kinase
3
ADP
Inactiveprotein
Activeprotein
Cellularresponse
Phosphorylation cascade
ATP
PPP i
ADPATP
PPP i
ADPATP
PPP i
P
P
P
Small Molecules and Ions as Second Messengers
• Second messengers are small, nonprotein, water-soluble molecules or ions
• The extracellular signal molecule that binds to the membrane is a pathway’s “first messenger”
• Second messengers can readily spread throughout cells by diffusion
• Second messengers participate in pathways initiated by G-protein-linked receptors and receptor tyrosine kinases
Cyclic AMP
• 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
ATP Cyclic AMP AMP
Adenylyl cyclase
PyrophosphateP P i
Phosphodiesterase
H2O
• Many signal molecules trigger formation of cAMP
• Other components of cAMP pathways are G proteins, G-protein-linked receptors, and protein kinases
• cAMP usually activates protein kinase A, which phosphorylates various other proteins
• Further regulation of cell metabolism is provided by G-protein systems that inhibit adenylyl cyclase
cAMP
ATPSecondmessenger
First messenger(signal moleculesuch as epinephrine)
G-protein-linkedreceptor
G protein
Adenylylcyclase
Proteinkinase A
Cellular responses
GTP
Calcium ions and Inositol Triphosphate (IP3)
• Calcium ions (Ca2+) act as a second messenger in many pathways
• Calcium is an important second messenger because cells can regulate its concentration
ATP
EXTRACELLULARFLUID
ATP
Mitochondrion
Ca2+
pump
Plasmamembrane
CYTOSOL
Endoplasmicreticulum (ER)
Ca2+
pump
Ca2+
pump
High [Ca2+]Key
Nucleus
Low [Ca2+]
• A signal relayed by a signal transduction pathway may trigger an increase in calcium in the cytosol
• Pathways leading to the release of calcium involve inositol triphosphate (IP3) and diacylglycerol (DAG) as second messengers
CYTOSOL
Ca2+Endoplasmicreticulum (ER)
IP3-gatedcalcium channel
IP3 (secondmessenger)
DAG
PIP2G-protein-linkedreceptor Phospholipase C
G protein
Signal molecule(first messenger)
EXTRACELLULARFLUID
GTP
Ca2+ (secondmessenger)
Variousproteinsactivated
Cellularre-sponses
Cytoplasmic and Nuclear Responses
• Ultimately, a signal transduction pathway leads to regulation of one or more cellular activities
• The response may occur in the cytoplasm or may involve action in the nucleus
• Many pathways regulate the activity of enzymes
Binding of epinephrine to G-protein-linked receptor (1 molecule)
Reception
Transduction
Inactive G protein
Active G protein (102 molecules)
Inactive adenylyl cyclase
Active adenylyl cyclase (102)
ATP
Cyclic AMP (104)
Inactive protein kinase A
Inactive phosphorylase kinase
Active protein kinase A (104)
Active phosphorylase kinase (105)
Active glycogen phosphorylase (106)
Inactive glycogen phosphorylase
Glycogen
Response
Glucose-1-phosphate(108 molecules)
• Many other signaling pathways regulate the synthesis of enzymes or other proteins, usually by turning genes on or off in the nucleus
• The final activated molecule may function as a transcription factor
ReceptionGrowth factor
Receptor
Phosphorylationcascade
Transduction
CYTOPLASM
Inactivetranscriptionfactor
Activetranscriptionfactor
PResponse
Gene
mRNA
DNA
NUCLEUS
Fine-Tuning of the Response
• Multistep pathways have two important benefits:
– Amplifying the signal (and thus the response)
– Contributing to the specificity of the response
Signal Amplification
• Enzyme cascades amplify the cell’s response
• At each step, the number of activated products is much greater than in the preceding step
The Specificity of Cell Signaling
• Different kinds of cells have different collections of proteins
• These differences in proteins give each kind of cell specificity in detecting and responding to signals
• The response of a cell to a signal depends on the cell’s particular collection of proteins
• Pathway branching and “cross-talk” further help the cell coordinate incoming signals
Signalmolecule
Receptor
Relaymolecules
Response 1 Response 2 Response 3
Cell B. Pathway branches,leading to two responses
Cell A. Pathway leads to a single response
Cell C. Cross-talk occursbetween two pathways
Response 4 Response 5
Activationor inhibition
Cell D. Different receptorleads to a different response
Signaling Efficiency: Scaffolding Proteins and Signaling Complexes
• Scaffolding proteins are large relay proteins to which other relay proteins are attached
• Scaffolding proteins can increase the signal transduction efficiency
Signalmolecule
Plasmamembrane
Receptor
Scaffoldingprotein
Threedifferentproteinkinases
Termination of the Signal
• Inactivation mechanisms are an essential aspect of cell signaling
• When signal molecules leave the receptor, the receptor reverts to its inactive state
Animations and Videos
• Biomembranes II: Membrane Dynamics and Communication
• Bozeman - Cell Communication
• Bozeman - Evolutionary Significance of Cell Communication
• Cell Junctions
• Tight Junctions
• Desmosomes
• Gap Junctions
Animations and Videos
• Bozeman - Signal Transduction
• Second Messengers (cAMP and Ca+2 Pathways)
• Chemical Synapse – 1
• Chemical Synapse – 2
• Voltage-Gated Channels and the Action Potential
• Signal Transduction Pathway
• Signaling by Secreted Molecules
• Signal Transduction
Animations and Videos
• 2nd Messenger
• Signal Amplification – 1
• Signal Amplification – 2
• Hormonal Communication
• Mechanism of Steroid Hormone Action
• Mechanism of Thyroxine Action
• Action of Epinephrine on a Liver Cell
• Action of Glucocorticoid Hormone
Animations and Videos
• Intracellular Receptor Model
• Mechanism of Action of Lipid-Soluble Messengers
• Mechanism of Thyroxine Action
• Mechanism of Steroid Hormone Action
• Lipid Soluble Hormone
• Chapter Quiz Questions – 1
• Chapter Quiz Questions - 2