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THIRD EDITION
HUMAN PHYSIOLOGY
AN INTEGRATED APPROACH
Dee Unglaub Silverthorn, Ph.D.
Chapter 6
Communication, Integration,
and Homeostasis
PowerPoint® Lecture Slide Presentation by
Dr. Howard D. Booth, Professor of Biology, Eastern Michigan University
Copyright © 2004 Pearson Education, Inc., publishing as Benjamin Cummings
About this Chapter
• How cells communicate
• Electrical and chemical signals
• Receptor types and how they function
• Local regulation of cells
• Modification of receptors and signals
• Homeostatic balance depends on communication
• Feedback regulates integration of systems
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Overview of Cell to Cell Communication:
• Chemical
• Autocrine & Paracrine: local signaling
• Endocrine system: distant, diffuse target
• Electrical
• Gap junction: local
• Nervous system: fast, specific, distant target
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Gap Junctions and CAMs
• Protein channels connexin
• Direct flow to neighbor
• Electrical- ions
(charge)
• Signal chemicals
• CAMs
• Need direct surface
contact
• Signal chemical
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Figure 6-1a, b: Direct and local cell-to-cell communication
Fig 3-6
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Mucin-like glycoproteins
(Sialyl-Lewis X PSL-1 &
ESL-1)
Integrins
CAMS
Selectins
f
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Adhesion
• Mediated by integrins ICAM-1 and VCAM-1
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Paracrines and Autocrines
• Local communication
• Signal chemicals
diffuse to target
• Example: Cytokines
• Autocrine–receptor
on same cell
• Paracrine–
neighboring cells
Figure 6-1c: Direct and local cell-to-cell communication
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Long Distance Communication: Hormones
• Signal Chemicals
• Made in endocrine
cells
• Transported via
blood
• Receptors on
target cells
Figure 6-2a: Long distance cell-to-cell communication
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Long Distance Communication:
Neurons and Neurohormones
• Neurons
• Electrical signal down axon
• Signal molecule (neurotransmitter) to target
cell
• Neurohormones
• Chemical and electrical signals down axon
• Hormone transported via blood to target
6-2
b: Long
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distance cell-to-cell communication
Long Distance Communication:
Neurons and Neurohormones
Figure 6-2b, c: Long distance cell-to-cell communication
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Signal Pathways
• Signal molecule (ligand)
• Receptor
• Intracellular signal
• Target protein
• Response
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Figure 6-3: Signal pathways
Receptor locations
• Cytosolic or Nuclear
• Lipophilic ligand
enters cell
• Often activates gene
• Slower response
• Cell membrane
• Lipophobic ligand
can't enter cell
• Outer surface
receptor
• Fast response
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Figure 6-4: Target cell receptors
Membrane Receptor Classes
• Ligand- gated channel
• Receptor enzymes
• G-protein-coupled
• Integrin
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Membrane Receptor Classes
Figure 6-5: Four classes of membrane receptors
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Signal Transduction
• Transforms signal
energy
• Protein kinase
• Second messenger
• Activate proteins
• Phosporylation
• Bind calcium
• Cell response
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Figure 6-8: Biological signal transduction
Signal Amplification
• Small signal produces
large cell response
• Amplification enzyme
• Cascade
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Figure 6-7: Signal amplification
Receptor Enzymes
• Transduction
• Activation
cytoplasmic
• Side enzyme
• Example:
Tyrosine kinase
Figure 6-10: Tyrosine kinase, an example of a receptor-enzyme
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G-Protein-coupled Receptors
• Hundreds of types
• Main signal transducers
• Activate enzymes
• Open ion channels
• Amplify:
• adenyl cyclase-cAMP
• Activates synthesis
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G-Protein-coupled Receptors
Figure 6-11: The G protein-coupled adenylyl cyclase-cAMP system
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serine (Ser)
threonine (Thr)
H
H
H3N+
C
COO
H3N+
C
COO
CH2
CH OH
OH
CH3
Many enzymes are regulated by covalent
attachment of phosphate, in ester linkage, to
the side-chain hydroxyl group of a particular
amino acid residue (serine, threonine, or
tyrosine).
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O
Protein Kinase
OH + ATP
Protein
Protein
O
P
O + ADP
O
H2O
Pi
Protein Phosphatase
 A protein kinase transfers the terminal
phosphate of ATP to a hydroxyl group on a
protein.
 A protein phosphatase catalyzes removal of
the Pi by hydrolysis.
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O
Protein Kinase
OH + ATP
Protein
Protein
O
P
O + ADP
O
H2O
Pi
Protein Phosphatase
Protein kinases and phosphatases are themselves
regulated by complex signal cascades. For
example:
 Some protein kinases are activated by Ca++calmodulin.
 Protein Kinase A is activated by cyclicAMP (cAMP).
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Adenylate Cyclase
(Adenylyl Cyclase) catalyzes:
ATP  cAMP + PPi
Binding of certain
hormones (e.g.,
epinephrine) to the outer
surface of a cell activates
Adenylate Cyclase to form
cAMP within the cell.
Cyclic AMP is thus considered
to be a second messenger.
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NH2
cAMP
N
N
N
N
H2
5' C 4'
O
O
O
H
H 3'
O
P
O-
H
1'
2' H
OH
NH2
Phosphodiesterase enzymes cAMP
catalyze:
cAMP + H2O  AMP
The phosphodiesterase that
cleaves cAMP is activated by
phosphorylation catalyzed by
Protein Kinase A.
Thus cAMP stimulates its
own degradation, leading to
rapid turnoff of a cAMP signal.
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N
N
N
N
H2
5' C 4'
O
O
O
H
H 3'
P
O
O-
H
1'
2' H
OH
G Protein Signal Cascade
Most signal molecules targeted to a cell bind at the cell
surface to receptors embedded in the plasma membrane.
Only signal molecules able to cross
the plasma membrane (e.g., steroid
hormones) interact with intracellular
receptors.
A large family of cell surface
receptors have a common structural
motif, 7 transmembrane a-helices.
Rhodopsin was the first of these to
have its 7-helix structure confirmed
by X-ray crystallography.
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Rhodopsin
PDB 1F88
The signal is usually passed from a 7-helix receptor to an
intracellular G-protein.
 Seven-helix receptors are thus called GPCR, or
G-Protein-Coupled Receptors.
 Approx. 700-1000 different GPCRs are encoded in the
human genome.
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 G-proteins are heterotrimeric, with 3 subunits a, b, g.
 A G-protein that activates cyclic-AMP formation within
a cell is called a stimulatory G-protein, designated Gs
with alpha subunit Gsa.
 Gs is activated, e.g., by receptors for the hormones
epinephrine and glucagon.
The b-adrenergic receptor is the GPCR for
epinephrine.
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Stimulatory and Inhibitory G Proteins
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hormone
signal
outside
GPCR
The a subunit of
a G-protein (Ga)
binds GTP, &
can hydrolyze it
to GDP + Pi.
plasma
membrane
agga
AC
GDP bbGTP
GTP
GDP
cytosol
ATP cAMP + PPi
a & g subunits have covalently attached lipid anchors that
bind a G-protein to the plasma membrane cytosolic surface.
Adenylate Cyclase (AC) is a transmembrane protein, with
cytosolic domains forming the catalytic site.
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hormone
signal
outside
GPCR
plasma
membrane
agga
AC
GDP bbGTP
GTP
GDP
cytosol
ATP cAMP + PPi
The sequence of events by which a hormone
activates cAMP signaling:
1. Initially Ga has bound GDP, and a,b, & g
subunits are complexed together.
Gb,g, the complex of b & g subunits, inhibits Ga.
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hormone
signal
outside
GPCR
plasma
membrane
agga
AC
GDP bbGTP
GTP
GDP
cytosol
ATP cAMP + PPi
2. Hormone binding, usually to an extracellular domain
of a 7-helix receptor (GPCR), causes a conformational
change in the receptor that is transmitted to a G-protein
on the cytosolic side of the membrane.
The nucleotide-binding site on Ga becomes more accessible to
the cytosol, where [GTP] > [GDP].
Ga releases GDP & binds GTP (GDP-GTP exchange).
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hormone
signal
outside
GPCR
plasma
membrane
agga
AC
GDP bbGTP
GTP
GDP
cytosol
ATP cAMP + PPi
3. Substitution of GTP for GDP causes another
conformational change in Ga.
Ga-GTP dissociates from the inhibitory bg complex
& can now bind to and activate Adenylate Cyclase.
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hormone
signal
outside
GPCR
plasma
membrane
agga
AC
GDP bbGTP
GTP
GDP
cytosol
ATP cAMP + PPi
4. Adenylate Cyclase, activated by the
stimulatory
Ga-GTP, catalyzes synthesis of
cAMP.
5. Protein Kinase A (cAMP Dependent Protein
Kinase) catalyzes transfer of phosphate from ATP
to serine or threonine residues of various cellular
proteins, altering their activity.
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Turn off of the signal:
1. Ga hydrolyzes GTP to GDP + Pi. (GTPase).
The presence of GDP on Ga causes it to
rebind to the inhibitory bg complex.
Adenylate Cyclase is no longer activated.
2. Phosphodiesterases catalyze hydrolysis of
cAMP  AMP.
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Small GTP-binding proteins include (roles indicated):
 initiation & elongation factors (protein synthesis).
 Ras (growth factor signal cascades).
 Rab (vesicle targeting and fusion).
 ARF (forming vesicle coatomer coats).
 Ran (transport of proteins into & out of the nucleus).
 Rho (regulation of actin cytoskeleton)
All GTP-binding proteins differ in conformation depending
on whether GDP or GTP is present at their nucleotide
binding site.
Generally, GTP binding induces the active state.
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 Cholera toxin catalyzes covalent modification of Gsa.
• ADP-ribose is transferred from NAD+ to an arginine residue at the
GTPase active site of Gsa.
• ADP-ribosylation prevents GTP hydrolysis by Gsa .
• The stimulatory G-protein is permanently activated.
 Pertussis toxin (whooping cough disease) catalyzes ADP-ribosylation at
a cysteine residue of the inhibitory Gia, making it incapable of
exchanging GDP for GTP.
• The inhibitory pathway is blocked.
 ADP-ribosylation is a general mechanism by which activity of many
proteins is regulated, in eukaryotes (including
well as in prokaryotes.
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mammals) as
ADP Ribosylation
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Signal amplification is an important feature
of signal cascades:
 One hormone molecule can lead to
formation of many cAMP molecules.
 Each catalytic subunit of Protein Kinase A
catalyzes phosphorylation of many proteins
during the life-time of the cAMP.
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G-Protein Coupled Receptors
and Second Messenger Systems
neurotransmitter - hormone
G-protein coupled receptor – 7 TM receptors
heterotrimeric G-proteins (abg) - GTPases
enzymes
ion channels
change in membrane potential
or resistance
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second
messenger
systems
enzymes
{
{
adenylate cyclase
guanylate cyclase
phospholipase C
cAMP
cGMP - NO
IP3/DAG – [Ca2+]i
Heterotrimeric
G-Proteins and Receptors
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Cummings of the Cell, 3 rd Ed., Fig. 15-23.
Alberts
et
al.,
Molecular
Biology
Diversity in the GPCR Signaling Pathways
Receptor isoforms
Adrenergic (norepinephrine)
a 6 isoforms
b3
Muscarinic acetylcholine
5 isoforms
Dopamine
5 isoforms (D1, D5 vs D2, D3, D4)
tissue expression
pharmacology
G-protein isoforms
G-protein subunit isoforms (Gs, Gi, Gq)
15 a
6b
effectors
12 g
a vs bg effectors
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G-Protein Coupled Receptors (GPCR) – 7 TM Receptors
Many classification schemes for GPCRs
ligands
small molecules
peptides
proteins
receptor structure
sequence similarity
size of extracellular domain
location of ligand binding site
extracellular domain
membrane-spanning domain
heterotrimeric G-proteins
Gs, Gi, Go
Alberts et al., (1994) Molecular Biology of the Cell,
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3rd
edn,
Figure
15-17
Very Partial List of GPCR Ligands
Huge gene superfamily
700-1000 GPCR genes in human genome
~2% of human genome
Small Molecules
epinephrine/norepinephrine
dopamine
acetylcholine - muscarinic
serotonin – 5-hydroxytryptamine
histamine
glutamate (metabotropic)
GABA type B
Ca2+
adenosine
ATP
leukotrienes
cannabinoids
taste receptors – sweet, bitter
odorants
retinal – light receptors/rhodopsin
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Peptides
angiotensin II
vasopressin/ADH
gastrin
secretin
cholecystokinin
prolactin
oxytocin
somatostatin
enkephalins/opiates
Proteins
chemokines
parathyroid hormone
thyroid stimulating hormone
thrombin
endothelin
Hormones with Second Messanger activity
Second Messenger
Examples of Hormones Which Utilize This
System
Cyclic AMP
Epinephrine and norepinephrine, glucagon,
luteinizing hormone, follicle stimulating
hormone, thyroid-stimulating hormone,
calcitonin, parathyroid hormone, antidiuretic
hormone
Protein kinase activity
Insulin, growth hormone, prolactin, oxytocin,
erythropoietin, several growth factors
Calcium and/or phosphoinositides
Epinephrine and norepinephrine,
angiotensin II, antidiuretic hormone,
gonadotropin-releasing hormone, thyroidreleasing hormone.
Cyclic GMP
Atrial naturetic hormone, nitric oxide
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GPCR’s are Major Drug Targets
Partial list of diseases and conditions treated in part by drugs that target GPCRs
allergies
anaphylactic shock
asthma
cardiac arrhythmias
congestive heart failure
coronary artery disease/angina
hypertension
hypotension/shock syndromes
peptic ulcer disease
schizophrenia
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Phosphatidylinositol Signal Cascades
O
O
R1
C
H2C
O
O
C
CH
H2C
R2
O
O
P
O
O
OH
2
phosphatidylinositol
H
H
1
6
H
OH
OH
H
OH
5
H
3
H
4
OH
Some hormones activate a signal cascade based
on the membrane lipid phosphatidylinositol.
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Phosphatidylinositol Signal Cascade: Phospholipase C, Inositol
Trisphosphate (IP3), Ca2+ and Diacylglycerol, Protein Kinase C (PKC)
Ca++
A
R
PLC
Gq
DAG
PKC
PIP2
Protein
IP3
Protein-P
Endoplasmic Reticulum
Ca++
PLC – phospholipase C
PIP2 – phosphatidylinositol bisphosphate
IP3 – inositol trisphosphate
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DAG – diacylglycerol
PKC – protein kinase C
O
O
R1
C
H2C
O
O
C
CH
H2C
R2
O
O
P
O
O
OH
2
H
PIP2
phosphatidylinositol4,5-bisphosphate
H
1
H
OH
3
H
6
OH
H
4
OPO32
5
H
OPO32
Kinases sequentially catalyze transfer of Pi from ATP to OH
groups at positions 5 & 4 of the inositol ring, to yield
phosphatidylinositol-4,5-bisphosphate (PIP2).
PIP2 is cleaved by the enzyme Phospholipase C.
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O
O
Different isoforms of
Phospholipase C have
different regulatory
domains, & thus respond
to different signals.
A G-protein, Gq
activates one form of
Phospholipase C.
R1
C
H2C
O
O
C
CH
H2C
cleavage by
Phospholipase C
R2
O
O
P
O
O
OH
2
H
PIP2
phosphatidylinositol4,5-bisphosphate
H
1
H
OH
3
H
6
OH
H
OPO32
5
H
4
OPO32
When a particular GPCR (receptor) is activated, GTP exchanges
for GDP. Gqa-GTP activates Phospholipase C.
Ca++, which is required for activity of Phospholipase C,
interacts with () charged residues & with Pi moieties of the
phosphorylated inositol at the active site.
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OPO32 H
OH
2
H
1
6
H
OH
OH
H
3
H
OPO32
O
5
H
4
OPO32
IP3
inositol-1,4,5-trisphosphate
O
R1
C
H2C
O
O
C
CH
H2C
OH
diacylglycerol
Cleavage of PIP2, catalyzed by Phospholipase C,
yields 2 second messengers:
 inositol-1,4,5-trisphosphate (IP3)
 diacylglycerol (DG).
Diacylglycerol, with Ca++, activates Protein
Kinase C, which catalyzes phosphorylation of
several cellular proteins, altering their activity.
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R2
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Katzung,
Basic
and
Clinical
Pharmacology, 2001, p. 123
Ca++
Ca++-release channel
IP3
Ca
ATP
calmodulin
Ca
++
endoplasmic
reticulum
Ca++-ATPase
++ ADP + Pi
IP3 activates Ca++-release channels in ER membranes.
Ca++ stored in the ER is released to the cytosol, where it
may bind calmodulin, or help activate Protein Kinase C.
Signal turn-off includes removal of Ca++ from the cytosol
via Ca++-ATPase pumps, & degradation of IP3.
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Transduction Reviewed
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Figure 6-14: Summary of signal transduction systems
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Novel Signal Molecules
• Calcium: muscle contraction
• Channel opening
• Enzyme activation
• Vesicle exocytosis of Nitric Oxide (NO)
• Paracrine: arterioles
• Activates cAMP
• Brain neurotransmitter
• Carbon monoxide (CO)
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Novel Signal Molecules
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Figure 6-15: Calcium as an intracellular messenger
Lipid Paracrines
The Fatty Acid Arachidonate is often esterified to the hydroxyl on C2
of glycophospholipids, especially phosphatidyl inositol.
Arachidonate is released from phospholipids by hydrolysis catalyzed
by Phospholipase A2. Corticosteroids are anti-inflammatory because
they prevent inducable Phospholipase A2 expression, reducing
arachidonate release.
http://www.rpi.edu/dept/bcbp/molbiochem/MBWeb/mb2/part1/prostag.htm
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http://www.answers.com/topic/phospholipase-a2-1
Lipid Paracrines
• Arachidonic acid:
second messenger,
forms paracrines
• Leukotrienes:
bronchioconstrictor,
to anaphylaxis
• Prostaglandins–
sleep, inflammation,
pain, fever
• Thromboxanes–
blood clotting
Figure 6-16: The arachidonic acid cascade produces lipid messengers
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Mechanism of Action of Common OTC Drugs
• Nonsteroidal anti-inflammatory drugs such as
aspirin and derivatives of ibuprofen inhibit
Cyclooxygenase activity of PGH2 Synthase. They
inhibit prostaglandin formation involved in fever,
pain and inflammation and inhibit blood clotting
by blocking thromboxane formation in blood
platelets.
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Modulation of Signal Pathways by Ligands
• Multiple ligands
• Agonist- turn on
receptor
• Antagonist-block
receptor activity
Figure 6-17: Agonists and antagonists
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Modulation by Receptors
• Multiple receptors for a ligand: epinephrine
• Alpha receptor–vasoconstriction
• Beta receptor–vasodilation
• Receptor up-regulatilon: Grow more receptors
• Receptor down-regulation: Grow fewer receptor
• Excess stimulation
• Drug tolerance
• Endocytosis of ligand & receptor
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Modulation by Receptors
Figure 6-18: Target response depends on the target receptor
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Homeostasis and “Homeodynamic”
Figure 6-19: Tonic control
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Control Pathways
• Maintain homeostasis
• Local–paracrines
• Long-distance–reflex control
• Nervous
• Endocrine
• Cytokines
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Control Pathways
Figure 6-21: Comparison of local and reflex control
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Reflex Control
• Stimulus
• Sensory receptor
• Afferent path
• Integration center
• Efferent path
• Effector- target
cell/tissue
• Response (feedback
loop)
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Figure 6-22: Steps of a reflex
Types of Receptors: Membrane, CNS & Peripheral
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Figure 6-23: Multiple meanings of the word receptor
Homeostatic Setpoint
• Homeostatic range -oscillation around setpoint
• Change in setpoint
• Acclimatization
• Biorhythms
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Figure 6-25: Oscillation around the setpoint
Feedback Loops
• Negative: are homeostatic
• Response slows stimulation
• Return to optimal range
• Positive: stimulation drives more stimulation
• Feed forward: prepares body for change
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Feedback Loops
Figure 6-26: Negative and positive feedback
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Feedback Loops
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Figure 6-27: A positive feedback loop
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Summary
• Integration of systems uses local, endocrine and
nervous communications
• Signals travel via diffusion, gap junctions, axons,
and blood to target cells
• Receptor types and functions: binding,
transduction, amplification, activation, cell
responses
• Receptors are modulated by competition,
specificity, blocking, up– and down–regulation
• Concepts of homeostasis (homeodynamics)
• Reflex control pathways, types, feedback and
their regulation
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