PHYSIOLOGY INCLUDES

FUNCTIONS
MECHANISMS
that maintain homeostasis
(internal stability)


WE WILL LEARN HOW SMALL CHANGES IN A
MECHANISM ALTER FUNCTION &
DISRUPT INTERNAL STABILITY AND HOW THE
SYSTEM COMPENSATES TO MINIMIZE THE
DISRUPTION

Example on next slide

Maintain
homeostasis
Ex: Blood
pressure falls;
heart rate
increases to
compensate
and return
pressure to
normal. If
blood pressure
increases,
what change in
heart rate do
you expect to
occur to
restore
pressure to
normal?
Extracellular
fluid
Major Extracellular
fluid = Plasma = Liquid
part of the blood
Plasma
Tube of centrifuged blood red
cells
White
cells
Extra- and Intracellular
Fluids:
capillary
Gigantic
green
tissue cell
is shown
here.
Where
would
you draw
red blood
cells?
Chapter 2
SOLUTIONS, concentrations, pH - A review of chemistry:
Initially complete problem set # 1 problems 1-7 and #15
available on Blackboard. Other problems will be covered in Chapter 5
% solutions Ex. 20 % = 0.20 x volume of 100 ml = 20 ml. 20 %
also = 20 grams per 100 ml aqueous solution. Why? Because
water has density = 1 g/ml for wt/vol solution .
Molar solutions. If mol wt = 200, what is the molarity of this 20 % solution ?
First, think in terms of liters. If 20 g/100 ml, how many g per liter? How
many moles in 20 grams? Must divide 20 grams by _________?
Recall that molar or millimolar solutions are per liter:
Ex: 1 molar = 1 mol/liter and 1 mole = molec wt in g
1 milimolar = 1 millimol/liter = 10
-3
mol/liter
1 micromolar = 1 mol/liter = 10
-6
mol/liter
1 nanomolar = 1 nmol/liter = 10
-9
mol/liter
1 picomolar = 1 pmol/liter = 10
-12
mol/liter
Practice writing the concentration of one solution in various units, such as
M, mM, nM, and pM. [Ex. A 1 molar solution is a 1000 mM solution.
1 mM solution is a 0.001 molar solution.] See problem set. You should be
able to make these conversions quickly.
Problems

If you are in a research laboratory, and you need
to make one liter of a 0.35 M solution of CaCl
2
,
what would you need to look up to know how
many grams of CaCl
2
to weigh?


Suppose you also need a 0.35 M solution of the
same substance. How would you dilute the 0.35
M solution to achieve this?

Other problems are in the problem set. It is
important to solve all of these to be sure you
solve do a new problem with similar logic
BIOMOLECULES

Proteins Carbohydrates Lipids Nucleotides

Glycogen Triglycerides RNA/DNA
ATP, cAMP
Amino Acids Polysaccharides fatty acids
+
Disaccharides glycerol

Monosaccharides Steroids
Eicosanoids
Phospholipids
More Chemistry Review
What are some of the enzymes that modify these
molecules? Ex: A lipase or trypsin or a nuclease has
what effect on some the above molecules? A
phosphorylase does what? A phosphatase does what?
Enzyme Kinetics or any type of Saturation kinetics Rate reaches a
plateau because something is limited (saturated) Ex: an enzyme is
saturated with substrate or an antibody is saturated with antigen. Km =
substrate concentration need to achieve a Rate = Vmax. Note on next
slides how saturation kinetics applies to many physiological reactions:
Ex: Hb-O
2
binding, hormone-receptor binding, antigen-antibody binding,
carrier-mediated transport of substances into cells. A lower Km indicates
that less substrate is needed to achieve a rate = Vmax.
Km
%
Hormone
receptor
binding
[ Hormone ]
What is saturated?
%
antigen
antibody
binding
[ Antigen ]
What is saturated

What is limiting?
i.e., what becomes
saturated in each
example?
What was saturated
in the example on
the previous slide?

You can draw a
similar curve for
binding of O
2
to
hemoglobin

In the graph of
HB/binding, O
2
is on
the x axis. What
becomes saturated?
%
Hormone
receptor
binding
Kd [ Hormone ]
Receptor is saturated
%
antigen
antibody
binding
Kd [ Antigen ]
Antibody is saturated

Kd = hormone or
antigen concentration
needed for maximal
binding. Kd =
concentration needed
for maximal binding.
Binding affinity = 1/Kd

If a hormone has a low
affinity, the Kd will be
high; i.e., more of the
hormone is needed for
maximal binding.

Conversely, if you know
that the Kd of a
hormone is low, its
affinity must be high.
Affinity reflects strength of binding.

Affinity is proportional to 1/Km or 1/Kd

Ex: If Km or Kd of A = 10
-9
, its affinity ~ 10
9
If Km or Kd of B = 10
-6
, affinity ~ 10
6

Affinity is not defined in units It is a relative strength of
binding estimated from Km or Kd.

Ex. You are trying to purchase a drug that binds to a particular heart
receptor that you are studying in the lab. The drugs for this receptor are
expensive, and you want to use as little of the drug as possible and still
obtain adequate binding to the receptor. Would you purchase a drug with
a Kd of 10
-9
or a Kd of 10
-12
? What do Kd and affinity tell you about the
amount of a substance needed?
A drug with a higher affinity, has a higher potency. If a compound has a
higher affinity, is the Kd higher or lower or unchanged?
How does affinity relate to the amount of drug needed for max binding
?
Carrier-mediated transport of substrate into a cell. Rate
of transport reaches a maximum when the carrier
becomes saturated. Transport Km = Concentration of
substrate when Rate = Vmax
-- If Competitor is present
more substrate required to
achieve same transport rate
Km of original substrate
increases
Km Km if competitor present
What
happens
in these
reactions
if another
substance
competes
for the
binding
sites?
Rate of
transport
[ substrate ]
What if simple diffusion (shown above) in which
no carrier is needed?

What happens to the rate (above) as the substrate
concentration increases?

What can you conclude about how carriers affect
the maximal rate of transport?
Please note that we have covered only SELECTED parts of
Chapters 1 and 2. It is not wise to waste time studying
sections that we did NOT cover or to work extra text
problems, as these will NOT be on exams.

Your exams will cover material and problems that are
emphasized on Blackboard, but not a memorized version of
the material. Exams often will require you to use the
material to solve NEW questions and problems that you
have never seen previously. This requires EXTRA
STUDYING AFTER you have memorized new terms and
basic facts. This requires you to understand lots of details,
not a general over-view.

PLEASE WORK THE PROBLEMS, STUDY THE MATERIAL AND ASK
QUESTIONS EACH WEEK PREFERABLY AFTER EACH LECTURE.
THERE IS NOT TIME DURING THE LAST WEEK BEFORE AN EXAM
TO LEARN A SUFFICIENT LEVEL OF DETAIL.
Review functions of cell organelles in chap. 3
Not for an exam, but to catch-up on terminology
examples: mitochondria, golgi, lysosomes

Review the structure of the cell membrane,
especially functions of membrane proteins:


Examples
Include:
Receptors,
G-proteins,
channels
Cell junctions: Tight junctions Gap junctions
prevent movement form bridge
of substances to allow rapid
between cells transport
between cells
[Gap junctions are similar to open channels].

A channel is a protein pore that allows water and/or
selected substances to cross a cell membrane

Most channels are gated (opened and closed by specific
mechanisms). A ligand is a substance that binds to
another substance. A ligand gated channel is opened or
closed when a particular substance (the ligand) binds to
it. A voltage-gated channel opens or closes when the
membrane voltage reaches a certain level.

A transport carrier (often called a transporter) is a protein
in the membrane that directly binds a substance (the
substrate) on one side of the membrane, then changes
shape and delivers the substance to the other side of the
membrane. Note that the substrate is the substance
being transported it is not a ligand regulator
Transporting epithelial cells - substances diffuse through these cells
by diffusion or active transport by various mechanisms through
channels or by transporters or directly through the lipid membrane if
lipid soluble.
Exchange-epithelia (ex. Capillary epithelia) have leaky gaps or pores
that permit substances to move between cells.
Epithelial cell secretions: Endocrine substances (hormones) are
secreted into blood and Exocrine substances into a duct or lumen.
Apical membrane
lumen
Basolateral
Membrane
blood
In the previous slide Look at the picture.
Note that the substance moved through more
than one membrane in order to travel from
the lumen of the intestine to the lumen of the
capillary. Did the molecules move through
any large open pores? Located where?

What would happen if the pores were tight
junctions rather than pores?
Apoptosis

Programmed
Cell Death regulated by
multiple signals. The DNA
condenses, the cell shrinks
and pulls away from
neighboring cells

Ap - o-TOE - sis
app = away
ptosis = falling

Ex: Another use of ptosis :
Ptosis of the eyelids =
droopy eyelids due to
neuromuscular disorders
Necrosis

Cellular death from
trauma, toxins,
lack of oxygen

Cells lyse (rupture)
If you squash a cell,
will you cause
apoptosis or
necrosis?
Review the various types of

connective tissues

muscles

neural tissues

NOT for an exam in this course, but this is
USEFUL background information and may help
you to perform better on exams such as the GREs
or DATs or MCATs
CELL SIGNALING MECHANISMS Chap. 6
1. Direct cell to cell communication through gap junctions
Direct transfer of substances. Ex. Very rapid transfer of ions
between heart cells permits the cells to function as a single
unit.
2. Indirect communication by signaling molecules or
first messengers, which are released from a cell and bind to
a receptor.
Release of Signal Binds production of second
Signal molecule to Receptor messengers
Response
Any signal molecule (natural or synthetic molecule) that binds
to a receptor is a ligand for that receptor.
Mechanisms stimulated by the ligand/receptor complex are
signal transduction mechanisms. [Transducers are devices
that convert one type of signal to another]. Receptors are
sometimes referred to as transducers. Signal transduction
mechanisms may amplify the signal by producing multiple
molecules and actions.
Amplification: Single ligand stimulates multiple paths.
Define a ligand any substance that ?

Receptors on muscle convert an electrical signal from a
nerve into chemical stimulation of muscles mechanical
action. How does this fit with the definition of a
transducer?
Signal Molecules (Common Ligands)
Paracrine signal molecules are released by cells and
diffuse only to nearby cells

Autocrine molecules act on the same cells that
produced them.

Endocrine molecules (hormones) are transported
through the blood to target cells.
Exocrine??

Neurotransmitters are released by nerve endings and
diffuse across a synapse to another neuron or across
a neuro-target cell junction (ex. neuromuscular
junction) to reach the target cell.
Neurohormones are released by neurons into the
blood.
Make up an example to explain how insulin
produced by the pancreas could act as both an
endocrine regulator stimulating muscle or liver
cells and a pacracrine regulator acting on cells
where?
A ligand that gives a normal biological response (mimics the
normal ligand) is a receptor agonist. A ligand that binds to
a receptor but gives no response and blocks binding of other
ligands is a receptor antagonist. Note that the antagonist
prevents binding of the normal ligand. The antagonist
behaves as a competitive inhibitor.
Agonists compete with each other and with antagonists
for binding. How would the Kd of each agonist or
antagonist affect this competition?

Receptors exhibit saturation, specificity, and
competition. Ex: a ligand and an antagonistic ligand
(called the antagonist) compete for binding to the receptor.
Specificity means that a receptor will bind one ligand or one
group of ligands but not other types of molecules. What is
down-regulation and up-regulation of receptors? How is
receptor activity terminated? -- How do cells stop the
binding of the ligand to the receptor? Look up in text.
Binding of a ligand to a receptor. % Binding reaches a
maximum when the Receptor becomes saturated.
-- If Competitor is present, is
more or less of the original
ligand required to achieve
same % binding?
Kd Kd if competitor is present
%
Binding
Of ligand
to
Recept
[ ligand concentration ]
Common Signal Transduction Mechanisms:



Intracellular Receptor Mechanisms
Ligand enters cell to bind to
receptors inside cell


Membrane Receptor Mechanisms
Ligand binds to receptors in the
cell membrane
Ligands must be able to move into cells to bind to
intracellular receptors. Ligands for intracellular receptors
are lipophilic. Do large protein hormones as growth
hormone and insulin bind to intracellular receptors?

Intracellular ligand/receptor complexes may move to cell
nucleus and modify transcription of genes
Intracellular Receptors
Ion Integrin Enzyme G-protein- G-
channel receptor receptor linked protein
receptor receptor
Trans
Memb.
Domains


Intra-
Cellular
domains
Extracellular domains
Receptors in the cell membrane
A large
ligand
would
bind to
which
domain?
Membrane Receptor Mechanisms
Ligand binds to ? domain of receptors in the cell
membrane
Ex. Protein hormones and catecholamines, such as
epinephrine, bind to these membrane receptors

extracellular domain
Intracellular
domain
transmembrane
domain of receptor
Ligand-gated ion channels - The receptors are ion
channels;
Ex: . the ligand/receptor complex may open a
calcium channel permitting calcium to enter the cell.
Calcium may activate enzymes or open other
ion channels
Calcium

may bind to calmodulin
activation of Calcium/CalmodulinKinase (CamK)
Ligand
Receptor
Ca++

Ca++

Calmodulin
CamK
What is important
about the word
complex above?
If the ligand is
absent, will the
receptor do
anything? If the
receptor is
damaged, does the
ligand function?
Membrane Receptors that are Enzymes.

Binding of the ligand activates the
enzyme (activates this receptor).

Ex: several receptors are tyrosine kinases
that phosphorylate the tyrosines of
proteins, which in turn initiate other reactions
in the cell that lead to a biological response
Ligand Receptor


protein

phophorylated
protein
If the receptor is a kinase, binding of the ligand stimulates
the kinase. Kinases phosphorylate proteins.

Integrin receptors

On the extracellular side of the membrane the
integrin binds to proteins of the extracellular
matrix or to ligands such as antibodies.

On the cytoplasmic side of the membrane the
integrin binds to bridging proteins that attach to the
cytoskeleton.

Draw a diagram (cartoon) of the domains of
integrin receptors.

Integrin receptors mediate blood clotting, wound
repair, cell adhesion, and cell movement during
development.
Membrane Receptors linked to G-proteins (proteins
that bind GTP and then initiate reactions)

Receptors linked to the G
s
protein (see text
Figures)
Stimulate adenyl cyclase cAMP
activity of A-kinase = Kinase-A
protein phosphorylation response

Receptors linked to the G
i
protein
Inhibit adenyl cyclase
activity of A-kinase
cAMP response
Receptors linked to the G
q
protein (see text figures)
Stimulate phospholipase C
Breakdown of membrane phospholipid to 2
second messengers: diacylglycerol (DAG) and
inositol triiphosphate (IP3)

IP3 releases calcium from intracellular stores and
increases Calcium in the cell response

DAG sensitizes C-kinase to Calcium
+
protein
phosphorylation response

Receptor linked to RAS (a small G protein) activates a
mitogen-activated protein kinase (MAPK) series of
kinase activations responses (expecially growth
responses)


Multiple receptors for the same ligand may generate
different second messengers and different responses.

Examples (not to memorize):

Acetylcholine = Ach
Ach + M1 receptor IP3 and DAG
Ach + M2 receptor cAMP

Serotonin = 5HT
5HT +5HT1-A receptor cAMP
5HT +5HT1-C receptor IP3

List all of the kinases and their functions studied so far.
List all other enzymes & their functions mentioned.
What are the functions of IP3 and DAG? Why is
simultaneous action of these important?
Draw a large cell and add all of the receptor
mechanisms (all signal transduction mechanisms) that
you have learned. What pathway does the receptor
stimulate? For each receptor, what are the
intermediate molecules as IP3 and DAG and which
kinases are activated or inactivated?
extracellular
intracellular
transmembrane

This is an example
of Studying by
Mapping a
technique
recommended by
your text author
drawing diagrams
or flow charts to
summarize
information- not to
increase
information.

Response Loop
How does the mechanism promote homeostasis?
Feedback Loops
In a negative feedback loop, the response does what to the
stimulus?
Glucose


Insulin



Glucose
Open Na+ channels



Memb. Voltage change




Open more Na+ channels
Common Rare
Explain how negative feedback loops maintain homeostasis.
How do positive feedback loops affect homeostasis?