Cell Signalling Final 2013

8/17/2019 Cell Signalling Final 2013

1/117

Cell signalingby Chemical messengers

Dr. Maha Sallam

Professor of Biohemistry


2/117

Professor of Biohemistry

Objectives of studying hormones

1- Define signal transduction-!nderstand different classifications of hormones

"-Define hydro#hilic and li#o#hilic hormones andthe difference bet$een both grou#s.

%-&numerate ty#es of hormone rece#tors.

'- Study mechanism of action of li#o#hilichormones.

(- Study different second messengers ofhydro#hilic hormones) c*MP+c,MP+Ca+P".

- Study structure of insulin rece#tor / its

mechanism of action.


3/117

Signal transduction

0his is the #rocess by $hich eracellular signals

can be transduced 2converted 3 into intracellularchemical changes.0hese signals 2 chemical messengers3 include:

4ormones+ neurotransmitters+ gro$th factors+light ..etc


4/117

1. S#ecificity. *m#lification

". Desensiti5ation / ada#tation%. ntegration

6eatures of signal transduction

system


5/117

0here is a molecular Com#lementarity

bet$een the signal / 7ece#tor

that are #resent only in certain cellty#es.

1-Specificity


6/117

By &n5yme Cascades 8hen an &9:. 8ith a

signal rece#tor is activated+ it $ill activate

many molecules of a second &9:. / so on.

2-Amplification


7/117

8hen a signal is #resent continuously desensiti5ation

of rece#tor system results.

3-Desensitization & adaptation


8/117

0he ability of the system to

receive multi#le signals and

#roduce a res#onse a##ro#riate to

the needs of the cell.

4-Integration


9/117


10/117

Endocrine System includes:

Pituitary gland0hyroid gland Parathyroid glandsSu#rarenal gland 2 corte / medulla30estis / Ovaries slets of ;angerhans of Pancreas.2nsulin / glucagon)


11/117

4y#othalamous

PitutaryOvary

0estis

0hyroid

Su#rarenalgland

Posterior lobe*nterior lobe

vaso#ressin

Oytocin0S4*C04,ro$th 4Prolactin

6S4+;4

Mammarygland

Mammarygland


12/117


13/117

1. 0he islets of ;angerhans of #ancrease2nsulin / ,lucagon controlled by glucose

level3.. Su#rarenal medulla 2Catecholamine

controlled by sym#athetic nerves3.

". Parathyroid gland 2


14/117

Classification of hormonesthere are different ty#es ofclassifications:Based on distance

of action

Based on chemical

structure

Based on solubility&

Mechanism of action


15/117

AUTOCRIE

!ARACRIE

EDOCRIE

Based on distance

of action


16/117

AUTOCRINE4ormones that act on the cells that

secrete them e.g hy#othalamic and#ituitary hormones and their effecton their o$n cells.


17/117

P*7*C79&

4ormone arises from one cell and acts at a

near cell e.g #rostaglandines act as localhormones


18/117

Endocrine

4ormones secreted by endocrine glands+trans#orted in blood and act on distant targetorgans


19/117

Based on chemical structure


20/117

Lipophilic Hormonesphilic Hormones

Based on solubility &

Mechanism o action


21/117

H

;i#o#hilic 44ydro#hilic 4

Cell membrane

H

Outside the cell

nside the cellSecond messenger

0hat mediates 4ormone action


22/117

4ydro#hilic 4ormones ;i#o#hilic 4ormones

0hese are )#oly#e#tides+

#roteins+ glyco#rotein>s

and catecholamines

0hey are steroid

4ormones +0" +0% and

Calcitriol0hey are $ater soluble

can not cross cell

membrane

0hey are li#id soluble

can cross cell membrane

0hey do not need

trans#orter #roteins

0hey need trans#ort

#roteins

Short #lasma half life

2minutes3

;ong #lasma half life

!hours or days"Cell membrane rece#tors ntracellular rece#tors

Mediators 2 second messanger3

) c*MP+ c,MP+ Calcium+ P"

4ormone rece#tor com#le


23/117

Cell signaling#ecture $


24/117

H

;i#o#hilic 44ydro#hilic 4

Cell membrane

H

Outside the cell

nside the cellSecond messenger

0hat mediates 4ormone action


25/117

#$The cell membrane is ormed o :a- equal proportions of lipid, protein and

carbohydrates

b- amphipathic lipids, proteins and small amount of sugars

c- hydrophobic proteins and sugars

d- amphipathic lipids and sugars


26/117

2-The receptor of the lipophilic

hormone is present in A-cell membrane

B-mitochondria

-nucleus

!- cytoplasm

"- endoplasmic reticulum

#-ribosomes


27/117

3-The hydrophilic hormone

needs a$$$%%for its action A-cytoplasmic receptor

B- transporter protein

-&uclear receptor

!- second messenger


28/117

4ormonal rece#tors

0hey are Cell-associated recognition

molecules can recogni5e / bind s#ecific

hormones #resent at a very lo$concentration in the

etra cellular fluid


29/117

Biological intercellular chemical effect


30/117

*gonists

Molecules that bind therece#tors / induce all the#ost-rece#tor events that lead

to a biological effect.0he hormone itself is agonist


31/117

*ntagonists Molecules that bind the

rece#tors / #revent bindingof the hormone+ so bloc? the

biologic effects of thehormone0hey can be used as drugs.

,eneral structure of the rece#tor


32/117

,eneral structure of the rece#torReco%nition domain

Coulin% domain

Bind the hormone

'enerates the si%nal


33/117

*ny 7ece#tor must have

7ecognition domain)Bind the 4ormone.cou#ling domain) $hich transduce a s#ecific

signal to the interior of thecell giving the 4ormone

res#onse


34/117

(ormonal recetors

ntracellularrece#tors

Cell membranerece#tors


35/117

ntracellular 7ece#tors areeither:

9uclear*s thyroid hormone

rece#tors

Cyto#lasmic*s Steroidhormones


36/117

Cell Membrane rece#tors

Ser#entine7

7 $ithen5ymaticactivity

7 that activatecyto#lasmic

?inases

on channel7


37/117

on channel rece#tor


38/117

4ormone rece#tor regulation


39/117


40/117

#$Do$n 7egulation

1. Decreasing rece#tor number

. 2Slo$ ada#tation3.". 8hen target cell e#osed continuously to

elevated levels of the hormone.

%. 0he cell can #rotect itself againstecessive hormonal stimulation.

'. &.g nsulin / Catecholamines


41/117

7ece#tor mediated &9DOC@0OSS.

7ece#tors failed to recycle to cellsurface.

0hey are delivered to lysosomes 0o be

degraded $ith the hormone.


42/117


43/117

Steroid rece#tors are do$nregulated By nhibiting

transcri#tion of their 7ece#torm79*


44/117

)$!# regulation

ncreasing 7ece#tor Synthesis.

2slo$ ada#tation3

e.g Prolactin u# regulates itsrece#tor in mammary gland.


45/117

*$Desensiti5ation

0his usually involves #hos#horylation

of the rece#tor 27a#id ada#tation3


46/117

Mechanism of actionof hormones


47/117

;i#o#hilic 4ormones1-Steroid hormones,lucocorticoides 2cortisol3

Mineralocorticoides 2aldosterone3


48/117

ntracellular 7ece#tors areeither:

9uclear*s thyroid hormone

rece#tors

Cyto#lasmic*s Steroidhormones


49/117


50/117


51/117

(RE

S#ecific function

0hyroid hormones


52/117

0hyroid hormones


53/117

;ecture "


54/117

4ydro#hilic 4ormones


55/117

0hey have different second

messenger:c*MP

c,MP

Calcium and or Phos#hatidylinositol

inase or Phos#hatase


56/117

1-cA%! as a second messenger

*denylate Cascade mechanism

4ormones acting by this method),lucagon+ adrenergic catecholamines+calcitonin+ #arathyroid hormone + 6S4+

;4+ *C04+ 0S4


57/117

Serpentine Receptors


58/117

Serpentine Receptors

http://www.nature.com/nrm/journal/v2/n9/images/nrm0901_642a_i1.jpg


59/117

,- #rotein cou#led adenyl cyclase-

c*MP systemThis system is ormed o : +erentine recetor ,- helical se%ments

' rotein

a %uanosine nucleotide/bindin% rotein

Adenyl Cyclase En0.

(ormone


60/117


61/117

On restin% state -subunit is bindin% to '3


62/117


63/117

P* 2Protein inase *3


64/117

RR

CC

Phos#horylation of cellular #roteinsat seine or threonine **

0hat stimulate or inhibit some en5.

c*MP de#endant Protein ?inase &n5yme


65/117

&ffect of c*MP on transcri#tion

P* #hos#horylates C7&B 2c*MP7es#onse &lement Binding #rotein3 to be

a #otent transcri#tion factor


66/117


67/117

0hi 4 l i i i


68/117

0his 4ormonal action is terminaby)

1-,0Pase activity of E subunit that converts,0P into ,DP $ith re-association of thethree subunits to return to the resting state.

- Phos#hodiesterase that convert c*MP into'-*MP.

"-Phos#hatases remove #hos#hate from

#hos#horylated #roteins and thus terminatethe hormonal action.


69/117

Medical *##lications

0oins disru#t , #rotein


70/117

0oins disru#t , #roteinCholera toinsare en5ymescataly5e *DPribosylation ofE subunit of ,s

Of intestinalcells

A3$ Ribose

Bloc?ing ,0Pase activityContinuous activation of *denyl cyclase of intestinal cells

c*MP

Continuous secretion of C;- + 4CO" and $ater

Diarrhea / dehydration

9*D

9icotinamide

0oins disru#t , #rotein


71/117

0oins disru#t , #roteinPertussis toins secreted by Bordetella #ertussis areen5ymes cataly5e *DP ribosylation of E subunit of ,i

A3.$ Ribose

Preventing dis#lacement of ,DP by ,0P andbloc?ing inhibition of adenyl cyclase by ,i

c*MP

8hoo#ing cough sym#toms


72/117

;ecture %


73/117

),MP d


74/117

)$c,MP as a second messenger

0he rece#toritself hasen5yme activity:

,uanylatecyclase activity

*ctivation of c ,MPde#endant #rotein

?inase ,

'T

c'M


75/117

6actors that de#end on c,MP

as a second messenger Atrial natriuretic factor

A 'Atriopeptin)

itric O(ide O

0here are t$o ty#es of ,uanyl cyclase


76/117

y#

Nitric O4ide

AN5


77/117


78/117

*trial natriuretic factor*96 2*trio#e#tin3

*trial natriuretic 6actor Blood volume


79/117

*trial natriuretic 6actor Blood volume

7enal ecretion of 9a and $ater /induces vasodilatation decreasing

blood volume

c,MP

&ffect of atrial natriuretic factor


80/117

&ffect of atrial natriuretic factor0his #e#tide is #roduced in cardiac atrial

tissues. t binds to and activates themembrane-bound form of guanylyl cyclase inthe ?idney 2 cells of collecting ducts3.

increase of c,MP

9atriuresis+ diuresis+ vasodilation+ andinhibition of aldosterone secretion decreasing

blood volume ©


81/117

9itric Oide

9O


82/117


83/117

9itric Oidesynthase

Smooth muscle relaation and vasodilatation

endothelial cells

&'

c'M

Smooth muscle cell

Soluble guanyl

cyclase


84/117

Medical *##lications

Eect o NO9itro vasodilators as nitroglycerin are used to


85/117

9itro vasodilators as nitroglycerin are used totreat *ngina because they brea? do$n over

several hours #roducing a steady stream of 9O

ncrease c,MP by activating cyto#lasmic guanylylcyclase

*ctivates c,MP-de#endent #rotein ?inase 2P,3+$hich in turn #hos#horylates a number of smooth

muscle #roteins $ith

relaation of smooth muscle and vasodilation.


86/117

*$Calcium and or Phos#hatidylinositol as second messenger


87/117

*$Calcium and or Phos#hatidyl

inositol as second messenger

#hos#hatidylinositol- Ca

#ath$ay

&am#les of 4ormones acting by this method6E1 adrenergic catecholamines7

6vaso#ressin7 6oytocin

0y#es of #hos#holi#ases 2 &n5 hydrolyse #hos#holi#ids3


88/117

0y#es of #hos#holi#ases 2 &n5. hydrolyse #hos#holi#ids3

hoshatidylinositol 879 bishoshate


89/117

C

3A'

I*


90/117


91/117

(

hosholiase C

hoshatidylinositol 8.9 dishoshate

C


92/117

7ole of Calcium as a second


93/117

7ole of Calcium as a second

messengerCalcium release from its storage vesiclesincreasing its intracellular level 1GGGG times:

t affects target #roteins by:

#$Directly by activating certain en5ymes e.g#hos#hyrlase that hydroly5es glycogen

)$ndirectly through calmodulin 2regulatory#rotein3

Ca is umed inside Mitochonria And Endolasmic


94/117

Ca is umed inside Mitochonria And Endolasmic

Reticulum by AT deendant Ca;AT ase um

Cell

C l d li i f


95/117

Calmodulin is one ofCaHH- de#endant #roteins

Ca bindin% induces conormational

chan%es in calmodulin

*ctivation of Ca HHcalmodulin-de#endantinase

Phos#horylation of of s#ecific en5ymes

Ca)


96/117

Medical a##lications


97/117

Medical a##lications

Phorbol esters synt*etic compounds t*at


98/117

Phorbol esters synt*etic compounds t*atare potent acti+ators of !,C- T*ey

apparently mimic cellular diacylglycerol assecond messengers .ut unli/e naturallyoccurring diacylglycerols t*ey are not

rapidly meta.olized- 0y continuouslyacti+ating !,C t*ese synt*etic tumorpromoters interfere 1it* t*e normal

regulation of cell gro1t* and di+ision causingcancer%


99/117

;ecture '

8Second messenger is a


100/117

8$Second messenger is a

inase or Phos#hatase1-0he rece#tor is a tyrosineinase 2 ,ro$th factors+ nsulinetc 3.

-7ece#tor $ith no en5yme

activity but use cyto#lasmictyrosine ?inases 2 Ia?-S0*0s3e.g ,ro$th hormone3


101/117

#$0he rece#tor is a tyrosine inase

2 ,ro$th factors+ nsulin etc 3.

1-nsulin rece#torheterotetramer glyco#rotein


102/117

heterotetramer glyco#rotein

)ntracellular Bsubunits have

tyrosine ?inaseactivity and

auto#hos#orylation

sites

)&tracellular

E subunits thatbind to insulin

Insulin


103/117

Phos#hatase

De#hos#horylationof certain regulatory en5ymesregulating metabolic #ath$ays

inase

Protein Phos#horylation

!altering gene e#ression"

nsulin 7ece#tor Substrate-1


104/117


105/117


106/117

(a) : a cytoplasmic tyrosine )inase * an

acronym for (anus )inase+

(anus *to headed god of the oman+

.TATs : signal transducer and acti/ator oftranscription%


107/117


108/117

e/ision 0uestions


109/117

1-Insulin binding to α subunit of its

receptor will cause:

a- ADP ribosylation of α subunit

b- phosphorylation of tyrosine residues ofβ subunit

c- activation of GTPase activity of α

subunitd- dissociation of α subunit from β subunit


110/117

a- acti/ates cholinergic receptors

b-stimulates adenyl cyclase

c- inhibits &a,-ATase

d- inhibits /asopressin secretion

*$Cholera to4in


111/117

8$cAM deendant rotein =inase :

a-is formed of 2 and 2 subunits

b- can bind to 4 calcium ions

c- can phosphorylate many en5ymes d- is inhibited by phosphatase


112/117


113/117

$+teroid hormones act throu%h


114/117

,$ Inositol trihoshate acts as a

second messen%er to :

a- stimulate cA6 dependant protein

)inase

b-acti/ate a phosphodiesterase

c- acti/ate cyclo-o9ygenase


115/117

$Insulin actions include :

a- acti/ation of calmodulin proteinb- co/alent modification of many

en5ymes and altering genee9pression

c- increase intracellular c76

23A patient infected 1it* c*olera *ad +omiting diarr*eand de*ydration E(plain t*e .ioc*emical mec*anism


116/117

and de*ydration- E(plain t*e .ioc*emical mec*anismof diarr*ea and de*ydration-

$3 Discuss mec*anism of action of steroid *ormones-43 5i+e an account on 5 proteins-63 5i+e s*ort notes on protein /inase A73 E(plain t*e mec*anism of intracellular calcium

release and its role as a second messenger-835i+e s*ort notes on c 5%! as a second messenger-93 Discuss structure of insulin receptor and mec*anism

of action of insulin *ormone-

Thank you


117/117

Thank you

&

Good Luck

Cell Signalling Final 2013

Documents

Transcript of Cell Signalling Final 2013