Ligands and Signal Trans Duct Ion

8/8/2019 Ligands and Signal Trans Duct Ion

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Dept. of Natural

Sciences

University of St. La

Salle

Bacolod City


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Cell communication begins when a receptorprotein on the target cell receives an

incoming extracellular signal and converts it

to the intracellular signals that direct cell

behavior. Signal reception

and signal

transduction

are the events

referred to in

cell signaling.

CELL SIGNALING SYSTEM


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COMPONENTS OF A SIGNALING SYSTEM

1. LIGAND - a molecule that binds to a specific siteon another molecule, usually a protein receptor;

provides a signal or an external message to the

cell; also known as primary messenger

Peptides / Proteins- growth Factors

Amino acid derivatives - epinephrine, histamine Other small biomolecules - ATP

Steroids, prostaglandins

Gases - Nitric Oxide (NO)

Photons Damaged DNA

Odorants, tastants

2. RECEPTOR- typically an extracellular ligand-

binding molecule; a few are cytoplasmic forms


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The ligand binds to a

receptor protein

which activates an

signal transductionpathway that is

mediated by a seriesofintracellular

signaling proteins.

These interact with

target proteins,altering them to

change cell behavior.The repertoire of

changes a cell can

show depends on

which receptors itpossess, how these

are coupled to signaltransduction

pathways, and howthese are coupled to

gene regulation.


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In situations

where even low

concentrations

of a ligand will

result in binding

of most of the

cognate

receptors, the

receptor affinityis considered to

be high.

Low receptor

affinity occurs

when a highconcentration of

the ligand is

required for

most receptors

to be occupied.

A ligand binds its receptor through a

number of specific weak non-covalent

bonds by fitting into a specific binding

site or "pocket".


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With prolonged exposure to a ligand (and occupation

of the receptor) cells often become desensitized.

Desensitization of the cell to a ligand depends uponreceptor down-regulation by either:

oremoval of the receptor from the cell surface

(receptor-mediated endocytosis) or,

oalterations to the receptor that lower the affinity for

ligand or that render it unable to initiate thechanges in cellular function (such as

phosphorylation).

Desensitization may lead to tolerance, a phenomenon

that results in the loss of medicinal effectiveness ofsome medicines that are over prescribed.

Receptor binding activates a "preprogrammed"

sequence of signal transduction events that make

use of previously dormant cellular processes.


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Every cell type displays

a set of receptorproteins that enables it

to respond to a specificset of signal molecules

produced by other cells.

These signal molecules

work in combinations toregulate the behavior of

the cell. Cells mayrequire multiple signals

(blue arrows) to survive,

additional signals (red

arrows) to divide, andstill other signals (green

arrows) to differentiate.If deprived of survival

signals, most cells

undergo a form of cell

suicide known as

programmed cell death,

or apoptosis.


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Different ways in which signals maybe integrated:


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CELL SIGNALING CASCADES

They transform, or transduce, the signal

into a molecular form suitable for passing

the signal along or stimulating a response.

They relay the signal from the point in the

cell at which it is received to the point at

which the response is produced.

In many cases, signaling cascades also

amplify the signal received, making itstronger, so that a few extracellular signal

molecules are enough to evoke a largeintracellular response.

The signaling cascades can also distribute

the signal so as to influence several

processes in parallel: at any step in the

pathway, the signal can diverge and be

relayed to a number of different

intracellular targets, creating branches inthe information flow diagram and evoking a

complex response.

Each step in this signaling cascade is open

to modulation by other factors, including

other external signals, so that the effects of

the signal can be tailored to the conditions

prevailing inside or outside the cell.


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Intracellular signaling proteins act as molecular switches.

Intracellular signaling proteins can be activated by the addition of aphosphate group and inactivated by the removal of the phosphate. In some

cases, the phosphate is added covalently to the protein by a protein kinase

that transfers the terminal phosphate group from ATP to the signaling protein;

the phosphate is then removed by a protein phosphatase (A). In other cases, a

GTP-binding signaling protein is induced to exchange its bound GDP for GTP;

hydrolysis of the bound GTP to GDP then switches the protein off (B).


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Signals A and B may activate different cascades of proteinphosphorylations, each of which leads to the phosphorylation of protein

Y but at different sites on the protein (A). Protein Y is activated only when

both of these sites are phosphorylated, and therefore it is active onlywhen signals A and B are simultaneously present. Alternatively, signals A

and B could lead to the phosphorylation of two proteins, X and Z, which

then bind to each other to create the active protein XZ (B).

Some

intracellularsignaling proteins

serve to integrate

incoming

signals.


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May

involve

genes(e.g.,

increased

cell growth

and

division

Changes in cell

movement,

secretion, ormetabolism

(i.e., rapid

phosphorylation

of target

proteins)


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A.Hormones produced in endocrine glands are secreted into

the bloodstream and are often distributed widely

throughout the body.

B.Paracrine signals are released by cells into the

extracellular medium in their neighborhood and act locally.


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C. Neuronal signals or neurotransmitters are transmitted

along axons to remote target cells.

D. Cells that maintain an intimate membrane-to-membrane

interface can engage in contact dependent (juxtacrine)signaling.

Many of the same types of signal molecules are used for

endocrine, paracrine, and neuronal signaling.

The crucial differences lie in the speed and selectivity with

which the signals are delivered to their targets.


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Contact-dependent signaling controls nerve-cell production.The signals that control the process of nerve cell specialization

from an embryonic epithelial sheet are transmitted via direct cell

cell contacts: each future neuron delivers an inhibitory signal tothe cells next to it, deterring them from specializing as neurons

too. Both the signal molecule (Delta)

and the receptor molecule (Notch) are

transmembrane proteins. In mutants

where the mechanismfails, some cell

types (such as

neurons)

are produced

in great

excessat the

expense

of others.


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Acetylcholine can induce different responses in different target

cells. Different cell types are configured to respond to

acetylcholine in different ways. Acetylcholine binds to similar

receptor proteins on heart muscle cells (A) and salivary gland

cells (B), but it evokes different responses in each cell type.Skeletal muscle cells (C) produce a different type of receptor

protein for the same signal. The different receptor types generate

different intracellular signals, thus enabling the different types of

muscle cells to react differently to acetylcholine. (D) For such a

versatile molecule, acetylcholine has a fairly simple structure.

NEUROTRANSMITTERS


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Chemical signals known as hormones aresecreted by one tissue to regulate another tissue,

often over a distance.

Hormones are often transmitted by the

circulatory system.

Hormones control many physiological functions

including growth and development, rates of

physiological processes, concentrations of

sugars and minerals, and responses to stress.

Hormones can be amino acid derivatives(epinephrine), peptides (antidiuretic hormone,

vasopressin), proteins (insulin), or lipid-like

hormones including steroids (testosterone)

HORMONES


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Hormonal signals can be classified by the distance that

they travel to reach their target cells.

1.An endocrine hormone travels through the circulatorysystem and a paracrine hormone acts only upon near

by cells.

2.A paracrine hormone is roughly equal to a growth

factor.

3.Endocrine tissues secrete directly into the blood-stream and exocrine tissues into ducts for transport of

the secretions to other parts of the body.

oThe pancreas has both endocrine (insulin and

glucagon) and paracrine (digestive enzymes)

functions.oOnce in the circulatory system, the endocrine

hormones will eventually reach their target tissue(s)

such as heart and liver (epinephrine) or liver and

skeletal muscles (insulin).


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The steroid hormone

cortisol acts by activating

a gene regulatory protein.

Cortisol diffuses directlyacross the plasma

membrane and binds to

its receptor protein, which is

located in the cytosol. The

hormonereceptor complex

is then transported into the

nucleus via the nuclearpores. Cortisol binding

activates the receptor

protein, which is then able to

bind to specific regulatory

sequences in the DNA and

activate gene transcription.

The receptors for cortisoland some other steroid

hormones are located in the

cytosol; those for the other

signal molecules of this

family are already bound to

DNA in the nucleus.


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GROWTH FACTORS

Growth factors act as messengers. In addition to nutrients, cell often need growth factors to

grow including: Platelet-derived growth factor (PDGF),

Insulin, insulin-like growth factor 1 (IGF-1), fibroblast

growth factor (FGF), epidermal growth factor (EGF),

nerve growth factor (NGF) These RTK ligands function in much more than growth

and cell division.


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FGFRs are important in the development of mesoderm, the embryonic tissue

that eventually becomes muscle, cartilage, bone and blood cells. A mutant

receptor that, due to dimerization with normal versions of FGFR, has a dominant

inhibitory effect upon the normal activity is a dominant negative mutation.

Disruption of growth factor signaling

through RTKs can have dramatic

effects on embryonic development.

The fibroblast growth factors (FGFs)

and fibroblast growth factor

receptors (FGFRs) function in both

embryonic and adult signaling.


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A dominant negative

mutant version of FGFR

mRNA injected into frogeggs cause the failure of

mesodermal tissue to

develop and produces

tadpoles with heads butno bodies. In humans,

defects in FGFRs lead to

thanatophoric dysplasia

severe bone

abnormalities (fatal in

infancy) and

achondroplasia

(dwarfism).


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Ca+2 levels in the cytoplasm is normally kept low (10-4) by Ca+2

pumps in the plasma membrane (out of the cell) and by sodium-

calcium exchangers a) out of the cell, b) into the endoplasmic

reticulum (ER) lumen and c) into the mitochondrion.

Ca+2 stores can be released from the ER by the InsP3 receptor

channel and ryanodine receptor channel which opens in the

presence of Ca+2 itself (Ca+2 -induced Ca+2 release).

The release of Ca+2

ions is a key event

in many signaling

processes.

Intracellular

concentrations can

be followed by

injection of Ca+2

indicator

fluorescent dyes,presence of ligand

or increase in InsP3

and monitoring the

increase in

fluorescence. The Ca+2 ionophore

releases Ca+2from

the intracellular

stores that mimics

effect of InsP3

activation.

Ca+2 ions act to

regulate many

cellular functions.

CALCIUM AS A SIGNAL


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Although other proteins bind Ca+2 to control

activity, most often binding to the protein

calmodulin, forming a Ca+2-calmodulin

complex is an intermediate step.

When Ca+2 ions are

present, two bind

each globular end(4 in total); the

helical arm region

then changes

conformation (the

active complex) and

then wraps aroundthe calmodulin-

binding site of

target protein

kinases and

phosphataseswhich may vary

depending upon the

target cell (different

cells have different

responses).


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Fertilization of animal eggs reveals an important

example of calcium-mediated signal transduction

after a receptor-ligand interaction. Initially the

sperm binds the eggs surface at the membrane and

within 30 seconds, a wave of calcium release

spreads from the site of sperm contact.

Two main events in fertilization rely on calcium release:

Calcium stimulates the fusion of the cortical granules with the eggs

plasma membrane to alter the coat surrounding the egg to help prevent

the binding of another sperm cell to the egg (slow block to polyspermy).

Calcium initiates egg activation, the resumption of metabolic processes.


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The conversion of glucose

into pyruvate is thus

accelerated, resulting in an

increase in the

concentration of ATP in thecytosol (2). The binding of

ATP to ATP-sensitive K

channels closes these

channels (3), thus reducing

the efflux of K ions from the

cell. The resulting small

depolarization of the

plasma membrane (4)

triggers the opening of

voltage-sensitive Ca+2

channels (5). The influx of

Ca+2 ions raises the

cytosolic Ca+2concentration, triggering

the fusion of insulin-

containing secretory

vesicles with the plasma

membrane and the

secretion of insulin (6).

Secretion of insulin from pancreatic cells in

response to a rise in blood glucose. The entry ofglucose into cells is mediated by the GLUT2

glucose transporter (1). A rise in extracellular

glucose from 5 mM, (fasting state), causes a

proportionate increase in the rate of glucose entry.


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Nitric oxide (NO) is a toxic, short-lived gas molecule

and has been found to be a signaling molecule in the

cardiovascular system.

The binding of acetylcholine causes the release of

NO in vascular endothelialcells.

NO couples the G protein-linked receptor stimulation

in endothelial cells to relaxation of smooth muscle

cells in blood vessels.

Note that NO gas is highly toxic when inhaled andshould not be confused with nitrous oxide (N2O), also

known as laughing gas.

NITRIC OXIDE AS A SIGNAL


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Regulation of contractility of arterial smooth muscle by nitric oxide (NO) and cGMP.Upon activation by acetylcholine, NO diffuses from the endothelium and activates an

intracellular NO receptor with guanylyl cyclase activity in nearby smooth muscle cells.

The resulting rise in cGMP leads to activation of protein kinase G (PKG), relaxation of the

muscle, and thus vasodilation. The cell-surface receptor for atrial natriuretic factor (ANF)also has intrinsic guanylyl cyclase activity. Stimulation of this receptor on smooth muscle

cells also leads to increased cGMP and subsequent muscle relaxation.


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Odorants (scent

chemicals) activate Gsand adenylate cyclase

in scent-sensitive

nerve cells. cAMP thenopens a non-selective

cation channel in the

plasma membrane.


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Signaling systems and cell responses. Cells are vibrantly alertdetectors, sensing and interpreting information constantly to adjust to the

environment (1) and coordinate activities with surrounding cells. Cells can

become different, depending on the amount of a signal (2), with a larger

amount giving rise to one cell fate and a smaller amount to another. Newboundaries form between cells of different types, creating tissues and

demarcations within tissues. Different cell types are created by

combinations of transcription factors (3). Inhibitory signals emitted by

cells undergoing a differentiation step can prevent nearby cells from

making the same decision (4), thus preventing duplication of structures.

Cells generally integrate many signals in deciding how to proceed (5).


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Cells regulate programmed cell death (PCD) or apoptosis which

is a very ordered mechanism to prune away unneededstructures, control the number of cells in particular tissues, and

sculpt complex organs.

It is an important part of normal development (removal of

webbing of fingers and toes in embryos, extra neurons in infants

and old blood cells in adults).

There is some evidence that activation of the apoptosis pathway

in adult neurons is responsible for Alzheimers disease and CV

stroke.

The cell death program involves the activation specific

proteases known as caspases and procaspases.

The Fas ligand on the surface of lymphocytes bind the Fasreceptors on the infected cells surface.This results in the

clustering of Fas, the attachment of adaptor proteins and

assembly of the procaspases at this site. The procaspases

activate each other to start a cascade of events that ends in

apoptosis.

CELL SIGNALING AND APOPTOSIS


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http://www.sinauer.com/cooper/4e/animations1501.html



http://www.wiley.com/college/boyer/0470003790/animations/signal_

transduction/signal_transduction.htm

http://bcs.whfreeman.com/thelifewire/content/chp15/15020.html

http://www.whfreeman.com/kuby/content/anm/kb02an01.htm

http://www.bio.davidson.edu/courses/Immunology/Flash/MAPK.html

http://www.whfreeman.com/kuby/content/anm/kb02an01.htm

Documents

Ligands and Signal Trans Duct Ion