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8/17/2019 Cell Signalling Final 2013
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Cell signalingby Chemical messengers
Dr. Maha Sallam
Professor of Biohemistry
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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.
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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
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1. S#ecificity. *m#lification
". Desensiti5ation / ada#tation%. ntegration
6eatures of signal transduction
system
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0here is a molecular Com#lementarity
bet$een the signal / 7ece#tor
that are #resent only in certain cellty#es.
1-Specificity
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By &n5yme Cascades 8hen an &9:. 8ith a
signal rece#tor is activated+ it $ill activate
many molecules of a second &9:. / so on.
2-Amplification
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8hen a signal is #resent continuously desensiti5ation
of rece#tor system results.
3-Desensitization & adaptation
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0he ability of the system to
receive multi#le signals and
#roduce a res#onse a##ro#riate to
the needs of the cell.
4-Integration
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Endocrine System includes:
Pituitary gland0hyroid gland Parathyroid glandsSu#rarenal gland 2 corte / medulla30estis / Ovaries slets of ;angerhans of Pancreas.2nsulin / glucagon)
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4y#othalamous
PitutaryOvary
0estis
0hyroid
Su#rarenalgland
Posterior lobe*nterior lobe
vaso#ressin
Oytocin0S4*C04,ro$th 4Prolactin
6S4+;4
Mammarygland
Mammarygland
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1. 0he islets of ;angerhans of #ancrease2nsulin / ,lucagon controlled by glucose
level3.. Su#rarenal medulla 2Catecholamine
controlled by sym#athetic nerves3.
". Parathyroid gland 2
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Classification of hormonesthere are different ty#es ofclassifications:Based on distance
of action
Based on chemical
structure
Based on solubility&
Mechanism of action
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AUTOCRIE
!ARACRIE
EDOCRIE
Based on distance
of action
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AUTOCRINE4ormones that act on the cells that
secrete them e.g hy#othalamic and#ituitary hormones and their effecton their o$n cells.
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P*7*C79&
4ormone arises from one cell and acts at a
near cell e.g #rostaglandines act as localhormones
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Endocrine
4ormones secreted by endocrine glands+trans#orted in blood and act on distant targetorgans
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Based on chemical structure
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Lipophilic Hormonesphilic Hormones
Based on solubility &
Mechanism o action
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H
;i#o#hilic 44ydro#hilic 4
Cell membrane
H
Outside the cell
nside the cellSecond messenger
0hat mediates 4ormone action
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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
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Cell signaling#ecture $
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H
;i#o#hilic 44ydro#hilic 4
Cell membrane
H
Outside the cell
nside the cellSecond messenger
0hat mediates 4ormone action
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#$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
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2-The receptor of the lipophilic
hormone is present in A-cell membrane
B-mitochondria
-nucleus
!- cytoplasm
"- endoplasmic reticulum
#-ribosomes
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3-The hydrophilic hormone
needs a$$$%%for its action A-cytoplasmic receptor
B- transporter protein
-&uclear receptor
!- second messenger
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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
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Biological intercellular chemical effect
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*gonists
Molecules that bind therece#tors / induce all the#ost-rece#tor events that lead
to a biological effect.0he hormone itself is agonist
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*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
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,eneral structure of the rece#torReco%nition domain
Coulin% domain
Bind the hormone
'enerates the si%nal
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*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
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(ormonal recetors
ntracellularrece#tors
Cell membranerece#tors
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ntracellular 7ece#tors areeither:
9uclear*s thyroid hormone
rece#tors
Cyto#lasmic*s Steroidhormones
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Cell Membrane rece#tors
Ser#entine7
7 $ithen5ymaticactivity
7 that activatecyto#lasmic
?inases
on channel7
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on channel rece#tor
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4ormone rece#tor regulation
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#$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
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7ece#tor mediated &9DOC@0OSS.
7ece#tors failed to recycle to cellsurface.
0hey are delivered to lysosomes 0o be
degraded $ith the hormone.
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Steroid rece#tors are do$nregulated By nhibiting
transcri#tion of their 7ece#torm79*
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)$!# regulation
ncreasing 7ece#tor Synthesis.
2slo$ ada#tation3
e.g Prolactin u# regulates itsrece#tor in mammary gland.
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*$Desensiti5ation
0his usually involves #hos#horylation
of the rece#tor 27a#id ada#tation3
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Mechanism of actionof hormones
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;i#o#hilic 4ormones1-Steroid hormones,lucocorticoides 2cortisol3
Mineralocorticoides 2aldosterone3
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ntracellular 7ece#tors areeither:
9uclear*s thyroid hormone
rece#tors
Cyto#lasmic*s Steroidhormones
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(RE
S#ecific function
0hyroid hormones
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0hyroid hormones
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;ecture "
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4ydro#hilic 4ormones
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0hey have different second
messenger:c*MP
c,MP
Calcium and or Phos#hatidylinositol
inase or Phos#hatase
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1-cA%! as a second messenger
*denylate Cascade mechanism
4ormones acting by this method),lucagon+ adrenergic catecholamines+calcitonin+ #arathyroid hormone + 6S4+
;4+ *C04+ 0S4
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Serpentine Receptors
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Serpentine Receptors
http://www.nature.com/nrm/journal/v2/n9/images/nrm0901_642a_i1.jpg
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,- #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
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On restin% state -subunit is bindin% to '3
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P* 2Protein inase *3
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RR
CC
Phos#horylation of cellular #roteinsat seine or threonine **
0hat stimulate or inhibit some en5.
c*MP de#endant Protein ?inase &n5yme
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&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
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0hi 4 l i i i
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0his 4ormonal action is terminaby)
1-,0Pase activity of E subunit that converts,0P into ,DP $ith re-association of thethree subunits to return to the resting state.
- Phos#hodiesterase that convert c*MP into'-*MP.
"-Phos#hatases remove #hos#hate from
#hos#horylated #roteins and thus terminatethe hormonal action.
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Medical *##lications
0oins disru#t , #rotein
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0oins disru#t , #roteinCholera toinsare en5ymescataly5e *DPribosylation ofE subunit of ,s
Of intestinalcells
A3$ Ribose
Bloc?ing ,0Pase activityContinuous activation of *denyl cyclase of intestinal cells
c*MP
Continuous secretion of C;- + 4CO" and $ater
Diarrhea / dehydration
9*D
9icotinamide
0oins disru#t , #rotein
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0oins disru#t , #roteinPertussis toins secreted by Bordetella #ertussis areen5ymes cataly5e *DP ribosylation of E subunit of ,i
A3.$ Ribose
Preventing dis#lacement of ,DP by ,0P andbloc?ing inhibition of adenyl cyclase by ,i
c*MP
8hoo#ing cough sym#toms
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;ecture %
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),MP d
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)$c,MP as a second messenger
0he rece#toritself hasen5yme activity:
,uanylatecyclase activity
*ctivation of c ,MPde#endant #rotein
?inase ,
'T
c'M
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6actors that de#end on c,MP
as a second messenger Atrial natriuretic factor
A 'Atriopeptin)
itric O(ide O
0here are t$o ty#es of ,uanyl cyclase
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y#
Nitric O4ide
AN5
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*trial natriuretic factor*96 2*trio#e#tin3
*trial natriuretic 6actor Blood volume
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*trial natriuretic 6actor Blood volume
7enal ecretion of 9a and $ater /induces vasodilatation decreasing
blood volume
c,MP
&ffect of atrial natriuretic factor
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&ffect of atrial natriuretic factor0his #e#tide is #roduced in cardiac atrial
tissues. t binds to and activates themembrane-bound form of guanylyl cyclase inthe ?idney 2 cells of collecting ducts3.
increase of c,MP
9atriuresis+ diuresis+ vasodilation+ andinhibition of aldosterone secretion decreasing
blood volume ©
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9itric Oide
9O
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9itric Oidesynthase
Smooth muscle relaation and vasodilatation
endothelial cells
&'
c'M
Smooth muscle cell
Soluble guanyl
cyclase
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Medical *##lications
Eect o NO9itro vasodilators as nitroglycerin are used to
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9itro vasodilators as nitroglycerin are used totreat *ngina because they brea? do$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 $ith
relaation of smooth muscle and vasodilation.
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*$Calcium and or Phos#hatidylinositol as second messenger
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*$Calcium and or Phos#hatidyl
inositol as second messenger
#hos#hatidylinositol- Ca
#ath$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
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0y#es of #hos#holi#ases 2 &n5. hydrolyse #hos#holi#ids3
hoshatidylinositol 879 bishoshate
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C
3A'
I*
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(
hosholiase C
hoshatidylinositol 8.9 dishoshate
C
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7ole of Calcium as a second
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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
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Ca is umed inside Mitochonria And Endolasmic
Reticulum by AT deendant Ca;AT ase um
Cell
C l d li i f
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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)
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Medical a##lications
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Medical a##lications
Phorbol esters synt*etic compounds t*at
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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%
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;ecture '
8Second messenger is a
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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
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#$0he rece#tor is a tyrosine inase
2 ,ro$th factors+ nsulin etc 3.
1-nsulin rece#torheterotetramer glyco#rotein
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heterotetramer glyco#rotein
)ntracellular Bsubunits have
tyrosine ?inaseactivity and
auto#hos#orylation
sites
)&tracellular
E subunits thatbind to insulin
Insulin
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Phos#hatase
De#hos#horylationof certain regulatory en5ymesregulating metabolic #ath$ays
inase
Protein Phos#horylation
!altering gene e#ression"
nsulin 7ece#tor Substrate-1
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(a) : a cytoplasmic tyrosine )inase * an
acronym for (anus )inase+
(anus *to headed god of the oman+
.TATs : signal transducer and acti/ator oftranscription%
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e/ision 0uestions
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1-Insulin binding to α subunit of its
receptor will cause:
a- ADP ribosylation of α subunit
b- phosphorylation of tyrosine residues ofβ subunit
c- activation of GTPase activity of α
subunitd- dissociation of α subunit from β subunit
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a- acti/ates cholinergic receptors
b-stimulates adenyl cyclase
c- inhibits &a,-ATase
d- inhibits /asopressin secretion
*$Cholera to4in
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8$cAM deendant rotein =inase :
a-is formed of 2 and 2 subunits
b- can bind to 4 calcium ions
c- can phosphorylate many en5ymes d- is inhibited by phosphatase
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$+teroid hormones act throu%h
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,$ 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
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$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
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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
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Thank you
&
Good Luck