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Assumed BackgroundChapter 1 – intro to physiologycontrol systems and homeostasis

Chapter 2 – molecular interactionscellular chemistry, molecular bonds, biomolecules, acids / bases, protein interactions

Chapter 3 – membranes, cell anatomy / organelles

Chapter 4 – bioenergetics, cellular metabolismenzymes, ATP, gene transcription translation protein

Chapter 5 – membrane dynamicsdiffusion, active transport, carrier proteins, ion channels,endocytosis, osmosis, tonicity

Chapter 6 – cell-cell communicationsignal transduction, modulation of signal pathways

Outline of Rest of Intro Unit• What is physiology?

• Homeostasis

• Cell-cell communication revisited– signal transduction– modulation of signal pathways

• Homeostatic reflex pathways– Cannon’s Postulates– neural, endocrine and neuroendocrine reflex pathways

What is Physiology?

long answer:“the science of the mechanical, physical, bioelectrical, and biochemical functions of <organism of interest> in good health, their organs, and the cells of which they are composed”

short answer:“the science of the function of living systems”

Function and Process

• Function “why”– Why does the system exist?– Why does the event occur?

• Process “how” – How does a system work?

• physiological mechanisms

Homeostasis• maintenance of a relatively stable internal environment

(especially extracellular fluid)– oscillation around a set point

externalenvironment

intracellularfluid (ICF)

extracellular fluid (ECF)

Fig. 1.4

1854, Claude Bernard “la fixité du milieu intérieur”

1929, Walter Cannon “homeostasis”

‘homeo’ rather than homo similar, though not the same

Historical Interlude

published in 1932,$21 on amazon.ca

Walter Cannon 1871-1945

“flight or fight response”

- expanded on Bernard’s concept of homeostasis

Compensation fails

Internal changeresults in loss

of homeostasis

Organism inhomeostasis

Organism attemptsto compensate

Externalchange

Internalchange

Compensation succeeds

WellnessIllness or disease

Fig. 1.3

study of homeostatic mechanisms= physiology

failure to compensate for change= disease

study of failure to compensate= pathophysiology

Local versus Reflex Control

Brainevaluates the change and initiates a response.

Systemicchange in blood

pressure sensedhere.

Brain

LOCALCHANGE

LOCALRESPONSE

Blood vessels

REFLEXRESPONSE

initiated by cellsat a distant site.

cells near site of change initiate response.

cells at a distantsite control response.

Response

Stimulus

Integrating center

KEY

Fig. 1.8

Control Systems and Homeostasis

response loop:• stimulus, sensor, input signal, integrating centre, output

signal, target, response

feedback mechanisms:• negative feedback stabilizes variable• positive feedback reinforces stimulus – not homeostatic• feedforward control anticipates change

Response

Initialstimulus

Stimulus

Response

Initialstimulus

Stimulus

Response loopshuts off

Negative feedback: response counteractsstimulus, shutting off response loop

Positive feedback: response reinforces stimulus, sending variable farther from setpoint

Feedback cycleoutside factor isrequired to shut offfeedback cycle

Fig. 1.11

Cell-Cell Communication - Overview• 75 trillion cells in the human body

• homeostasis achieved by nervous and endocrine systems with their combination of electrical and chemical signals

– electrical signals – changes in membrane potential• restricted to nerve and muscle cells

– chemical signals are secreted into extracellular fluid by all cells• responsible for most communication

• cells that respond to signals are ‘target cells’

Cell-Cell Communication: long range

endocrine: chemical (‘hormone’) released into bloodstream and distributed throughout body

Fig. 6.114

Cell-Cell Communication: long rangeneural: electrical signal travels down neuron; reaches end and

is translated to chemical signal (neurotransmitter) which transmits information to next cell

neuro endocrine: electrical signal travels down neuron; reaches end and is secreted into blood

15

Fig. 6.1

What defines a ‘target’ cell?How can sending a signal throughout the entire body affect

only certain cells?

Only cells that have receptors for that signal will respond to it.signal molecule that binds to a particular receptor is its

ligand

Receptors are proteins thatproject to outside of the membrane, or are within the cell, in the cytoplasm

Chemical properties of signal molecules (ligands) determine what type of receptor they will interact with.

water soluble = hydrophilic = lipophobic surface receptorwater insoluble = hydrophobic = lipophilic intracellular receptor16

Location of Receptors

Lipophobic signal molecule

Receptor

Ligand-receptor complex

Rapid cellularresponses

Extracellular fluid

Intracellular fluid

Slower responsesrelated to changes

in gene activity

Receptor in cytosol

Receptorin nucleus

Lipophilic signalmolecules

Lipophobic signalmolecules

Cell membrane

Fig. 6.3a, b17

lipophilic = hydrophobic

lipophobic = hydrophilic

Types of Membrane Receptors

Cellmembrane

G protein

Channel Integrin

Enzyme

Anchorprotein

Cytoskeleton

Ionchannel

Enzyme-coupledreceptor

Integrinreceptor

G protein-coupledreceptor (GPCR)

18

Fig. 6.3c

Firstmessenger

Transducer

Secondmessengersystem

Targets

Signalmolecule

Membranereceptor protein

Intracellularsignal molecules

Targetproteins

binds to

activates

alter

create

Response Response

Fig. 6.5a

Signal Transduction

Signal Transduction

alter

signalmolecule

membrane receptor

signal transduction by proteins

amplifier enzymes

second messengermolecules

protein kinases Ca2+

phosphorylatedproteins

activated Ca2+-binding proteins

Extracellularfluid

Intracellularfluid

response

initiates

binds to

ionchannel

Fig. 6.5b20

Signal

Inactive A

Inactive B

Inactive C

Substrate

Conversion of substrateto product is the finalstep of the cascade.

Active A

Active B

Active C

Product

Fig. 6.6a

Signal Transduction Cascades

L

R

AE

Receptor-ligand complexactivates an

amplifier enzyme (AE).

One ligand is amplified into manyintracellular molecules.

Cellmembrane

ExtracellularFluid

IntracellularFluid

Fig. 6.6b

Signal transduction cascades provide amplification.

ATP

GTP

PI(membrane

phospholipid)

adenylylcyclase(membrane)

guanylyl cyclase(membrane)

guanylyl cyclase(cytosol)

phospholipase C(membrane)

GPCR

GPCR

enzyme-linkedreceptor

nitric oxide(NO)

activates proteinkinase A; binds to ion channels

activates proteinkinases

binds to ionchannels.

releases Ca2+ fromintracellular stores.

activates proteinkinase C

binds to calmodulin;binds to other proteins

phosphorylatesproteins; alterschannel opening

phosphorylatesproteins

alters channel opening

See Ca2+ effectsbelow.

phosphorylatesproteins

alters enzyme activity,exocytosis, musclecontraction, cyto-skeleton movement,channel opening

Ca2+

IP3

DAG

cyclic AMP

Ions

Lipid-derived

Nucleotides

SECONDMESSENGER

MADEFROM

AMPLIFIERENZYME

LINKEDTO ACTION EFFECTS

Components of Selected Signal Pathways

cyclic GMP

Fig. 6.6c

GPCR = G protein-coupled receptorIP3 = inositol trisphosphate; PI = phosphatidyl inositolDAG = diacylglycerol

see: 6.7, 6.8, 6.9, 6.11

Summary of Signal Transduction

Fig. 6.11

Modulation of Signal Pathways• one ligand may have several different types of receptors

– explains how same signal can have different effects in different cell types

• receptors exhibit saturation, specificity, competition for their ligands (and molecules similar to their ligands)– e.g. relative affinities of adrenergic receptors for epinephrine

versus norepinephrine– e.g. agonists and antagonists competing with endogenous

ligands

• cells can change their response to signals by changing receptor number or sensitivity– increase ↑ gene expression (up-regulation)– decrease internalize surface receptors (down-regulation)– change receptor sensitivity e.g. phosphorylation

25

More than one receptor for a particular ligand

Intestinalblood vessel

Skeletal muscleblood vessel

-Receptor response 2-Receptor response

Epinephrine + -Receptor

2-Receptor-Receptor

Epinephrine + 2-Receptor

Vessel constricts

Vessel dilates

ligand = epinephrine (fright or flight response)

Fig. 6.1326

Agonists and Antagonists

= natural (‘native’) ligand

structurally similar molecules may be able to compete for receptor binding sites

= similar molecule that activates receptor AGONIST; ANALOGUE; MIMIC

= molecule that is similar enough to native ligand to bind to receptor, but not activate it ANTAGONIST; BLOCKER

no responseresponse

27

similar to Fig. 6.14

28

Table 6.1

Many Diseases and Drugs Disrupt Signal Pathways

Cannon’s Postulates• the nervous system has a role in maintaining ‘fitness’

of the internal environment– coordinates responses that regulate blood volume,

blood pressure, osmolarity, body temp, etc

• some systems are under tonic control

• some systems are under antagonistic control

• one chemical signal can have different effects in different tissues“homeostatic agents antagonistic in one region of the body may be cooperative in another region”

‘Tonic’ Control

Time

Electricalsignals

fromneuron

Change in signal rate

TimeTime

Tonic control regulates physiological parameters in an up-down fashion.

Increased signal rate Decreased signal rate

Fig. 6.15a31

Antagonistic ControlAntagonistic neurons control heart rate:

some speed it up, while others slow it down.

Stimulation by parasympathetic nerves decreases heart rate.Stimulation by sympathetic nerves increases heart rate.

Heart beats Heart beats

Sympatheticneuron

Parasympatheticneuron

Fig. 6.15b32

Steps of a Reflex Pathway

SENSORor

RECEPTOR

AFFERENTPATHWAY

INTEGRATINGCENTER

EFFERENTPATHWAY

TARGET OREFFECTOR

RESPONSE

STIMULUS

Response loopFee

dbac

k lo

op

similar to Fig. 6.1633

sensors / detectors / receptors:• specialized cell types in strategic locations

(often in extracellular fluid)

examples of signals monitored:• chemicals - glucose, CO2, O2, Na+, Ca++

• hormones – via specific receptors

• osmolarity – cells that respond to swelling, shrinking

• blood volume/pressure – cells that respond to stretch

controller / integrating centre:• organ or gland• brain (often brain is cc’d but is not

necessary for homeostatic response

efferent output:• can be to particular cell type within an

organ or multiple organ systems

Fig. 6.17

Multiple Meanings of ‘Receptor’

A SimpleEndocrine Reflex

A Simple NeuralReflex

A Complex Neuro-endocrine Reflex

Response

Target

Target Target

Response Response

ReceptorReceptor

Internalor external

change

Internalor external

change

Internalor external

change

Input signal:sensory neuron

Input signal:sensory neuron

Endocrinesystem sensor-

integratingcenter

Nervoussystem

integratingcenter

Nervoussystem

integratingcenter

Output signal:hormone

Efferentneuron

Efferentneuron or

neurohormone

Endocrineintegrating

center

Output signal# 2: hormone

Fig. 6.18

Neural Versus Endocrine Control

Table 6.2

(Fig 6.19 – let’s come back to this one when we reach these types of pathways)