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Assumed Background
Chapter 1 intro to physiology control systems and homeostasis Chapter 2 molecular interactions cellular chemistry, molecular bonds, biomolecules, acids / bases, protein interactions Chapter 3 membranes, cell anatomy / organelles Chapter 4 bioenergetics, cellular metabolism enzymes, ATP, gene transcription translation protein Chapter 5 membrane dynamics diffusion, active transport, carrier proteins, ion channels, endocytosis, osmosis, tonicity Chapter 6 cell-cell communication signal 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 Cannons 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

external environment

extracellular fluid (ECF)

intracellular fluid (ICF)

Fig. 1.4

Historical Interlude
1854, Claude Bernard la fixit du milieu intrieur 1929, Walter Cannon homeostasis
homeo rather than homo similar, though not the same

Walter Cannon 1871-1945 flight or fight response - expanded on Bernards concept of homeostasis

published in 1932, $21 on amazon.ca

Organism in homeostasis

External change

Internal change

Internal change results in loss of homeostasis

study of homeostatic mechanisms = physiology failure to compensate for change = disease study of failure to compensate = pathophysiology

Organism attempts to compensate

Compensation fails

Compensation succeeds

Illness or disease

Wellness

Fig. 1.3

Local versus Reflex Control

Brain evaluates the change and initiates a response.
Systemic change in blood pressure sensed here. cells at a distant site control response. Blood vessels REFLEX RESPONSE initiated by cells at a distant site.

Brain

cells near site of change initiate response.

LOCAL CHANGE

LOCAL RESPONSE

KEY Stimulus Integrating center Response

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

Initial stimulus

Response loop shuts off

Response

Stimulus Negative feedback: response counteracts stimulus, shutting off response loop Initial stimulus

Response
Feedback cycle

outside factor is required to shut off feedback cycle

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

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. 6.1

14

Cell-Cell Communication: long range

neural: 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

Fig. 6.1

15

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 that project 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 receptor 16 water insoluble = hydrophobic = lipophilic intracellular receptor

Location of Receptors
Receptor in cytosol Receptor in nucleus

lipophilic = hydrophobic

lipophobic = hydrophilic

Lipophilic signal molecules

Lipophobic signal molecules

Slower responses related to changes in gene activity

Lipophobic signal molecule Extracellular fluid Receptor

Ligand-receptor complex

Fig. 6.3a, b

Intracellular fluid

Rapid cellular responses

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Types of Membrane Receptors

Channel Integrin

Cell membrane

Anchor protein
Enzyme G protein Cytoskeleton

Ion channel

Enzyme-coupled receptor

G protein-coupled receptor (GPCR)

Integrin receptor

Fig. 6.3c

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Signal Transduction
Signal molecule binds to Membrane receptor protein activates Intracellular signal molecules alter Target proteins create Response Response Targets Second messenger system Transducer First messenger

Fig. 6.5a

Signal Transduction
signal molecule
binds to

Extracellular fluid

membrane receptor
initiates

signal transduction by proteins amplifier enzymes

alter second messenger molecules protein kinases Ca2+

ion channel

Intracellular fluid

phosphorylated proteins

activated Ca2+binding proteins

Fig. 6.5b

response

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Signal Transduction Cascades

Signal

Inactive A

Active A

Inactive B

Active B

Inactive C

Active C

Substrate

Conversion of substrate to product is the final step of the cascade.

Product

Fig. 6.6a

Signal transduction cascades provide amplification.

Receptor-ligand complex activates an amplifier enzyme (AE).

Extracellular Fluid

L R

Cell membrane

AE
Intracellular Fluid

One ligand is amplified into many intracellular molecules.

Fig. 6.6b

Components of Selected Signal Pathways

SECOND MESSENGER
Nucleotides ATP cyclic AMP GTP cyclic GMP Lipid-derived IP3 DAG Ions Ca2+ PI (membrane phospholipase C phospholipid) (membrane) GPCR releases Ca2+ from See Ca2+ effects intracellular stores. below.

MADE FROM

AMPLIFIER ENZYME
adenylyl cyclase (membrane) guanylyl cyclase (membrane) guanylyl cyclase (cytosol)

LINKED TO
GPCR

ACTION
activates protein kinase A; binds to ion channels

EFFECTS
phosphorylates proteins; alters channel opening phosphorylates proteins alters channel opening

enzyme-linkedactivates protein receptor kinases nitric oxide binds to ion (NO) channels.

activates protein kinase C

binds to calmodulin; binds to other proteins

phosphorylates proteins
alters enzyme activity, exocytosis, muscle contraction, cytoskeleton movement, channel opening

GPCR = G protein-coupled receptor IP3 = inositol trisphosphate; PI = phosphatidyl inositol DAG = diacylglycerol

see: 6.7, 6.8, 6.9, 6.11

Fig. 6.6c

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
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More than one receptor for a particular ligand

ligand = epinephrine (fright or flight response)
-Receptor response -Receptor 2-Receptor response 2-Receptor Skeletal muscle blood vessel Epinephrine + 2-Receptor

Intestinal blood vessel Epinephrine + -Receptor

Vessel constricts Vessel dilates

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Fig. 6.13

Agonists and Antagonists

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

response

no response

= natural (native) ligand = 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

similar to Fig. 6.14

27

Many Diseases and Drugs Disrupt Signal Pathways

Table 6.1

28

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

Electrical signals from neuron

Time Change in signal rate

Increased signal rate

Decreased signal rate

Time

Time

Fig. 6.15a

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Antagonistic Control
Antagonistic neurons control heart rate: some speed it up, while others slow it down.

Parasympathetic neuron

Sympathetic neuron

Stimulation by sympathetic nerves increases heart rate. Heart beats

Stimulation by parasympathetic nerves decreases heart rate. Heart beats

Fig. 6.15b

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Steps of a Reflex Pathway

STIMULUS SENSOR or RECEPTOR AFFERENT PATHWAY

sensors / detectors / receptors: specialized cell types in strategic locations (often in extracellular fluid) examples of signals monitored: chemicals - glucose, CO2, O2, Na+, Ca++

Response loop

Feedback loop

hormones via specific receptors osmolarity cells that respond to swelling, shrinking

INTEGRATING CENTER

blood volume/pressure cells that respond to stretch

controller / integrating centre: organ or gland brain (often brain is ccd but is not necessary for homeostatic response efferent output: can be to particular cell type within an organ or multiple organ systems 33

EFFERENT PATHWAY TARGET OR EFFECTOR

RESPONSE

similar to Fig. 6.16

Multiple Meanings of Receptor

Fig. 6.17

A Simple A Simple Neural A Complex NeuroEndocrine Reflex Reflex endocrine Reflex

Internal or external change

Internal or external change

Receptor Input signal: sensory neuron

Internal or external change

Receptor Input signal: sensory neuron Nervous system integrating center Efferent neuron or neurohormone Endocrine integrating center Output signal # 2: hormone Target

Endocrine system sensorintegrating center Output signal: hormone Target

Nervous system integrating center Efferent neuron Target

Response

Response

Fig. 6.18

Response

Neural Versus Endocrine Control

(Fig 6.19 lets come back to this one when we reach these types of pathways)

Table 6.2