311Intro & Cell Signaling (1)

8/12/2019 311Intro & Cell Signaling (1)

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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 THEDISRUPTION

Example on next slide


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Extracellularfluid

Major Extracellular

fluid = Plasma = Liquid

part of the blood

Plasma

Tube of centrifuged blood redcells

Whitecells

Extra- and Intracellular

Fluids:

capillary

Giganticgreen

tissue cell

is shown

here.Where

would

you draw

red blood

cells?


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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? Howmany 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 = 10-3mol/liter

1 micromolar = 1 mol/liter = 10-6mol/liter1 nanomolar = 1 nmol/liter = 10-9mol/liter

1 picomolar = 1 pmol/liter = 10-12mol/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 beable to make these conversions quickly.


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Problems

If you are in a research laboratory, and you need

to make one liter of a 0.35 M solution of CaCl2,

what would you need to look up to know how

many grams of CaCl2 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


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BIOMOLECULES

Proteins Carbohydrates Lipids NucleotidesGlycogen Triglycerides RNA/DNA

ATP, cAMP

Amino Acids Polysaccharides fatty acids

+

Disaccharides glycerol

Monosaccharides Steroids

Eicosanoids

PhospholipidsMore 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?


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Enzyme Kinetics or any type of Saturation kineticsRate reaches a

plateau because something is limited (saturated)Ex: an enzyme issaturated 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-O2binding, hormone-receptor binding, antigen-antibody binding,

carrier-mediated transportof substances into cells. A lower Km indicatesthat less substrate is needed to achieve a rate = Vmax.

Km


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%

Hormone

receptorbinding

[ Hormone ]

What is saturated?

%

antigen

antibody

binding

[ Antigen ]

What is saturated

What is limiting?

i.e., what becomes

saturated in each

example?

What was saturatedin the example on

the previous slide?

You can draw asimilar curve for

binding of O2 to

hemoglobin

In the graph of

HB/binding, O2 is on

the x axis. What

becomes saturated?


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%

Hormone

receptorbinding

Kd[ Hormone ]

Receptor is saturated

%

antigen

antibody

binding

Kd [ Antigen ]

Antibody is saturated

Kd= hormone or

antigen concentration

needed for maximal

binding. Kd =

concentration neededfor maximal binding.

Binding affinity = 1/Kd

If a hormone has a lowaffinity, 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.


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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 ~ 109

If Km or Kd of B = 10-6, affinity ~ 106

Affinity is not defined in unitsIt 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 witha 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?


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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 rateKm of original substrateincreases

Km Km if competitor present

What

happensin these

reactions

if another

substance

competes for the

binding

sites?


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Rate of

transport

[ substrate ]

What if simple diffusion (shown above) in which

no carrier is needed?

What happens to the rate (above) as the substrateconcentration increases?

What can you conclude about how carriers affect

the maximal rate of transport?


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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 thematerial 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 WEEKPREFERABLY AFTER EACH LECTURE.

THERE IS NOT TIME DURING THE LAST WEEK BEFORE AN EXAMTO LEARN A SUFFICIENT LEVEL OF DETAIL.


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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


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Cell junctions: Tight junctions Gap junctions

prevent movement form bridge

of substances to allow rapid

between cells transport

between cells


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[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 ligandis 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-gatedchannel opens or closes when the

membrane voltage reaches a certain level.

A transport carrier (often called a transporter) is a proteinin 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 substancebeing transportedit is not a ligand regulator


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Transporting epithelial cells - substances diffuse throughthese cells

by diffusionor active transport by various mechanismsthroughchannels 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) aresecreted into blood and Exocrine substances into a duct or lumen.

Apical membrane

lumen

Basolateral

Membrane

blood


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In the previous slideLook at the picture.

Note that the substance moved through morethan 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?

A t i


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Apoptosis

Programmed

Cell Death regulated by

multiple signals. The DNAcondenses, 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 fromtrauma, toxins,

lack of oxygen

Cells lyse (rupture)

If you squash a cell,will you cause

apoptosis or

necrosis?


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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

C S G G C S S C 6


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CELL SIGNALING MECHANISMSChap. 6

1. Direct cell to cellcommunication 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 communicationby signaling molecules or

first messengers, which are released from a cell and bind to

a receptor.

Release of Signal Binds production of secondSignal molecule to Receptor messengers ResponseAny signal molecule (natural or synthetic molecule) that binds

to a receptor is a l igandfor that receptor.

Mechanisms stimulated by the ligand/receptor complex aresignal 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.


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Amplification: Single ligand stimulates multiple paths.

Define a ligandany 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?


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Signal Molecules (Common Ligands)

Paracrinesignal 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 transportedthrough the blood to target cells.

Exocrine??

Neurotransmittersare released by nerve endings anddiffuse across a synapseto another neuron or across

a neuro-target cell junction (ex. neuromuscular

junction) to reach the target cell.

Neurohormonesare released by neurons into the

blood.


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Make up an example to explain how insulin

produced by the pancreas could act as both anendocrine regulator stimulating muscle or liver

cells and a pacracrine regulator acting on cells

where?


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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.Specificitymeans 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 ofthe ligand to the receptor? Look up in text.

Binding of a ligand to a receptor % Binding reaches a


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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 com etitor is resent

%

Binding

Of ligandto

Recept

[ ligand concentration ]


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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

I t ll l R t


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Ligands must be able to move into cells to bind to

intracellular receptors. Ligands for intracellular receptorsare 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

Receptors in the cell membrane


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Ion Integrin Enzyme G-protein- G-

channel receptor receptor linked protein

receptor receptor

Trans

Memb.Domains

Intra-

Cellulardomains

Extracellular domains

Receptors in the cell membrane

A large

ligand

wouldbind to

which

domain?


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Membrane Receptor Mechanisms

Ligand binds to ?domain of receptors in the cell

membrane

Ex. Protein hormones and catecholamines, such asepinephrine, bind to these membrane receptors

extracellular domain

Intracellular

domain

transmembrane

domain of receptor


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Ligand-gated ion channels - The receptors are ion

channels;

Ex: . the ligand/receptor complexmay open a

calcium channelpermitting calcium to enter the cell.Calcium mayactivate enzymes or open other

ion channels

Calcium may bind to calmodulinactivation of Calcium/CalmodulinKinase (CamK)Ligand

ReceptorCa++

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?


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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


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If the receptor is a kinase, binding of the ligand stimulates

the kinase. Kinases phosphorylate proteins.


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Integrin receptors

On the extracellular side of the membranetheintegrinbinds to proteins of theextracellular

matrix or toligands such as antibodies.

On the cytoplasmic sideof the membranethe

integrin binds to bridging proteins that attach to the

cytoskeleton.

Draw a diagram (cartoon) of the domains of

integrin receptors.

Integrin receptorsmediate blood clotting, wound

repair, cell adhesion, and cell movementduring

development.


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Membrane Receptors linked to G-proteins(proteinsthat bind GTP and then initiate reactions)

Receptors linked to the Gsprotein (see text

Figures)

Stimulateadenyl cyclase cAMPactivity of A-kinase = Kinase-Aprotein phosphorylation responseReceptors linked to the Giprotein

Inhibit adenyl cyclase activity of A-kinasecAMPresponse

Receptors linked to the G protein (see text figures)


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Receptors linked to the Gqprotein (see text figures)

Stimulate phospholipase CBreakdown of membrane phospholipid to 2

second messengers: diacylglycerol (DAG)and

inositol triiphosphate (IP3)

IP3 releases calcium from intracellular storesand

increases Calcium in the cell responseDAGsensitizes C-kinaseto Calcium+proteinphosphorylation response

Receptor linked to RAS(a small G protein) activates amitogen-activated protein kinase (MAPK)series ofkinase activations responses (expecially growthresponses)


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Multiple receptors for the same ligandmay generate

different second messengers and different responses.

Examples (not to memorize):

Acetylcholine = Ach

Ach + M1 receptorIP3 and DAGAch + M2 receptorcAMPSerotonin = 5HT

5HT +5HT1-A receptorcAMP5HT +5HT1-C receptorIP3List 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?


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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 theintermediate molecules as IP3 and DAG and which

kinases are activated or inactivated?

extracellular

intracellulartransmembrane

This is an example

of Studying byMapping a

technique

recommended by

your text author

drawing diagramsor flow charts to

summarize

information- not to

increase

information.

Response Loop


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Response Loop

How does the mechanism promote homeostasis?

Feedback Loops


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Feedback LoopsIn a negative feedback loop, the response does what to the

stimulus?

Glucose

Insulin

Glucose

Open Na+ channels

Memb. Voltage change

Open more Na+ channel

Common Rare

E l i h ti f db k l i t i h t i

311Intro & Cell Signaling (1)

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