Download Cell-to-cell communication Transduction pathways

Cell-to-cell communication
Transduction pathways
L. 3. 13.09.10
Cellular Communication
 Everything in animal does involve communication
among cells
 Example: moving, digesting food
 Cell signaling – communication between cells
 Signaling cell sends a signal (usually a chemical)
 Target cell receives the signal and responds to it
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Types of Cell Signaling
 Direct
 Signaling cell and target cell connected by gap
junctions
 Signal passed directly from one cell to another
 Indirect
 Signaling cell releases chemical messenger
 Chemical messenger carried in extracellular fluid
 Some may be secreted into environment
 Chemical messenger binds to a receptor on target cell
 Activation of signal transduction pathway
 Response in target cell
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Indirect Signaling Over Short Distance
 Short distance
 Paracrine
 Chemical messenger diffuses to nearby cell
 Autocrine
 Chemical message diffuses back to signaling cell
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Indirect Signaling Over Long Distance
Long distances
 Endocrine System
 Chemical messenger (hormone) transported by
circulatory system
 Nervous System
 Electrical signal travels along a neuron and chemical
messenger (neurotransmitter) is released
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CHEMICAL REGULATORY AGENTS
Communication & Coordination
(C02, 02, H+)
(Ca2+)
cAMP
cGMP
ACh, GABA
not secreted by specific glands
non-specific metabolic by-products
intracellular messenger
ECF or SR
coupling agent
intracellular messenger
second messenger for many hormones
neurotransmitters
neuromodulators
insulin
estrogen, testosterone
antidiuretic hormone
bombykol
HORMONES
pheromone
Types of Cell Signaling
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Figure 3.1
Direct Signaling
 Gap junctions
 Specialized protein complexes create an aqueous pore
between adjacent cells
 Movement of ions between cells
 Changes in membrane potential
 Chemical messengers can travel through the gap
junction
 Example: cAMP
 Opening and closing of gap junction can be regulated
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GAP JUNCTIONS
cells coupled metabolically and
electrically via hydrophilic channels
Passage of:
- inorganic ions
- small water-soluble molecules:
amino acids
sugars
nucleotides
- electrical signals
-labile:
Fig. 3.2 The structure of gap junctions
close in response to
high [Ca2+]ICF or high [H+]ICF
Indirect Signaling
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Table 3.1
CELLULAR COMMUNICATION:
AUTOCRINE and PARACRINE CELL SIGNALING
Secreted chemical affects
secreting cell (autocrine)
nearby cell (paracrine)
Chemical Messengers
 Six classes of chemical messengers
 Peptides
 Steroids
 Amines
 Lipids
 Purines
 Gases
 Structure of chemical messenger (especially
hydrophilic vs. hydrophobic) affects signaling
mechanism
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Indirect Signaling
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Table 3.2
MECHANISM OF ACTION OF
hydrophilic chemical messengers
(e.g. LIPID-INSOLUBLE HORMONES)
peptides and proteins,
catecholamines
•usually not bound to carrier protein
•do not readily diffuse across membrane
•bind to membrane receptor
•H-R complex triggers production of 2nd
messenger
cAMP, cGMP (cyclic nucleotide
monophosphates)
IP3 (inositol phospholipids)
Ca2+ ions
•rapid, short-lived responses; usually metabolic
Transport of chemical messenger to the target cell
MECHANISM OF ACTION OF
hydrophobic chemical messengers
(e. g. LIPID-SOLUBLE HORMONES
steroid hormones
thyroid hormones
•bound to carrier protein in blood
•readily diffuse across membrane
•bind to cytoplasmic or nuclear receptor
•H-R complex binds to regulatory portions
of DNA
•stimulate (or inhibit) transcription of
specific genes
•and specific proteins
•effects persist for hours to days
Transport of chemical messenger to the target cell
HORMONES
•BIOLOGICALLY ACTIVE CHEMICALS
•SYNTHESIZED, STORED, AND SECRETED BY:
ENDOCRINE GLANDS
(ductless) e.g. pancreas, thyroid, gonad
NEUROSECRETORY CELLS e.g. supraoptic nuclei of hypothalamus
•SECRETED INTO BLOOD
(free or bound)
•LOW CIRCULATING TITRES
(e.g. insulin 5 X 10-12 M)
•SHORT BIOLOGICAL HALF-LIFE
e.g. insulin 5-8 minutes, testosterone 1 hour, FSH 3 hours, thyroxine 6 days
•PLASMA CLEARANCE BY: TARGET CELL UPTAKE
ENZYMATIC DEGRADATION (liver)
URINARY EXCRETION
STRUCTURAL CLASSIFICATION OF HORMONES
1. PEPTIDES & PROTEINS
3  >200 a.a.
peptide hormones
protein hormones (e.g. insulin)
2. AMINES
thyroid hormones
catecholamines
(e.g. epinephrine)
tyrosine precursor small, H20-soluble
3. STEROIDS
adrenal cortical hormones (e.g. cortisol)
gonadal hormones (e.g. estrogen, testosterone)
cyclic hydrocarbon derivatives
cholesterol precursor
lipid soluble
4. EICOSENOIDS (autocrine, paracrine)
prostaglandins
cyclic unsaturated fatty acids
Peptide/Protein Hormones
 2-200 amino acids long
 Synthesized on the rough ER
 Often as larger preprohormones
 Stored in vesicles
 Prohormones
 Secreted by exocytosis
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Peptide/Protein Hormones
 Hydrophilic
 Soluble in aqueous solutions
 Travel to target cell dissolved in extracellular fluid
 Bind to transmembrane receptors
 Signal transduction
 Rapid effects on target cell
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Synthesis & Secretion of Peptide Hormones
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Figure 3.4
Synthesis & Secretion of AVP
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Figure 3.5
Transmembrane Receptor
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Figure 3.6
Steroid Hormones
 Derived from cholesterol
 Synthesized by smooth ER or mitochondria
 Three classes of steroid hormones
 Mineralocorticoids
 Electrolyte balance
 Glucocorticoides
 Stress hormones
 Reproductive hormones
 Regulate sex-specific characteristics
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Synthesis of Steroid Hormones
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Figure 3.7
Steroid Hormones
 Hydrophobic
 Can diffuse through plasma membrane
 Cannot be stored in the cell
 Must be synthesized on demand
 Transported to target cell by carrier proteins
 Example: albumin
 Bind to intracellular or transmembrane receptors
 Slow effects on target cell (gene transcription)
 Stress hormone cortisol has rapid non-genomic effects
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Steroid Hormones
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Figure 3.8
Amine Hormones
 Chemicals that possess amine group (–NH2)
 Example: acetylcholine, catecholamines (dopamine,
norepinephrine, epinephrine), serotonin, melatonin,
histamine, thyroid hormones
 Sometimes called biogenic amines
 Some true hormones, some neurotransmitters, some
both
 Most hydrophilic
 Thyroid hormones are hydrophobic
 Diverse effects
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Other Chemical Messengers
 Eicosanoids
 Most act as paracrines
 Hydrophobic
 Often involved in
inflammation and
pain
 Example:
prostaglandins,
leukotrienes
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Figure 3.10
Other Chemical Messengers
 Gases
 Most act as paracrines
 Example: nitric oxide (NO), carbon monoxide
 Purines
 Function as neuromodulators and paracrines
 Example: adenosine, AMP, ATP, GTP
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Communication to the Target Cell
 Receptors on target cell
 Hydrophilic messengers bind to transmembrane
receptor
 Hydrophobic messengers bind to intracellular
receptors
 Ligand
 Chemical messenger that can bind to a specific
receptor
 Receptor changes shape when ligand binds
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Ligand-Receptor Interactions
 Ligand-receptor interactions are specific
 Only the correctly shaped ligand (natural ligand) can
bind to the receptor
 Ligand mimics
 Agonists – activate receptors
 Antagonists – block receptors
 Many ligand mimics act as drugs or poisons
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BINDING OF HORMONE TO
CELLULAR RECEPTOR
PRECEDES BIOLOGICAL
RESPONSE OF TARGET CELL
depends on:
3D structure of hormone
complementary structure of receptor
unique molecular shape discriminated
exclusively by specific receptor
Fig.3.11 Ligand-receptor interactions
Ligand-Receptor Binding
 L + R  L-R
 Formation of L-R complex causes response
 More free ligand (L) or receptors (R) will increase the
response
 Law of mass action
 Receptors can become saturated at high L
 Response is maximal
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Ligand-Receptor Binding
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Figure 3.12
Changes in Number of Receptors
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Figure 3.13a
Ligand-Receptor Dynamics
 Affinity of receptor
for ligand affects
number of
L-R complexes
 Higher affinity
constant (Ka)  
response
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Figure 3.13b
Changes in Number of Receptors
 Number of receptors affects number of L-R
complexes
 More receptors   L-R complexes   response
 Target cells can alter receptor number
 Down-regulation
 Target cell decreases the number of receptors
 Often due to high concentration ligand
 Up-regulation
 Target cell increases the number of receptors
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Fig. 3.1 Overview of cell signaling
NEURAL SIGNALING
Neuron -neurotransmitter released into
synaptic cleft (e.g. Ach)
NEUROENDOCRINE SIGNALING
Neurosecretory cell – specialized neuron;
hormone released into
blood stream (e.g. oxytocin)
ENDOCRINE SIGNALING
Non-neuronal; hormone released into
blood stream (e.g. insulin, testosterone)
Cells show morphological polarity
ENDOCRINE SIGNALING
Signal Transduction Pathways
 Convert the change in receptor shape to an
intracellular response
 Four components
 Receiver
 Ligand binding region of receptor
 Transducer
 Conformational change of the receptor
 Amplifier
 Increase number of molecules affected by signal
 Responder
 Molecular functions that change in response to signal
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Signal transduction pathways
Amplification by signal transduction pathways
Fig. 3.15
Types of Receptors
 Intracellular
 Bind to hydrophobic ligands
 Ligand-gated ion channels
 Lead to changes in membrane potential
 Receptor-enzymes
 Lead to changes in intracellular enzyme activity
 G-protein-coupled
 Activation of membrane-bound G-proteins
 Lead to changes in cell activities
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Types of Receptors
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Figure 3.16
Intracellular Receptors




Ligand diffuses across cell membrane
Binds to receptor in cytoplasm or nucleus
L-R complex binds to specific DNA sequences
Regulates the transcription of target genes
 increases or decreases production of specific mRNA
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Intracellular Receptors
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Figure 3.17
Ligand-Gated Ion Channels





Ligand binds to transmembrane receptor
Receptor changes shape opening a channel
Ions diffuse across membrane
Ions move “down” their electrochemical gradient
Movement of ions changes membrane potential
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Ligand-Gated Ion Channels
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Figure 3.19
Receptor Enzymes
 Ligand binds to transmembrane receptor
 Catalytic domain of receptor starts a
phosphorylation cascade
 Phosphorylation of specific intracellular proteins
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Receptor Enzymes
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Figure 3.20
G-Protein-Coupled Receptors
 Ligand binds to transmembrane receptor
 Receptor interacts with intracellular G-proteins
 Named for their ability to bind guanosine nucleotides
 Subunits of G-protein dissociate
 Some subunits activate ion channels
 Changes in membrane potential
 Changes in intracellular ion concentrations
 Some subunits activate amplifier enzymes
 Formation of second messengers
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G-Protein-Coupled Receptors
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Figure 3.25
Cyclic-AMP Signaling
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Figure 3.27
Second Messengers
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Table 3.3
Interaction Among Transduction Pathways
 Cells have receptors for different ligands
 Different ligands activate different transduction
pathways
 Response of the cell depends upon the complex
interaction of signaling pathways
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Regulation of Cell Signaling
 Cell signaling is important for regulation of
physiological processes
 Components of biological control systems
 Sensor
 Detects the level of a regulated variable
 Sends signal to an integrating center
 Integrating center
 Evaluates input from sensor
 Sends signal to effector
 Effector
 Target tissue that responds to signal from integrating
center
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Regulation of Cell Signaling
 Set Point
 The value of the variable that the body is trying to
maintain
 Feedback loops
 Positive
 Output of effector amplifies variable away from the set
point
 Positive feedback loops are not common in physiological
systems
 Negative
 Output of effector brings variable back to the set point
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