Post on 26-Feb-2018
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Principles of Signal Transduction: Objectives
1. Be able to compare and contrast the overall properties ofendocrine and synaptic signaling mechanisms.
a. Endocrine Signaling echanism:i. !ormone is secreted by an endocrine gland and is
carried" via the bloodstream" to a distant target cell
ii. Signaling is S#O$1. %elies on passive di&usion and blood 'o(
iii. Signals are )*#+TE1. %eceptors have high speci,city and a-nity for
the signala. hemically based speci,city and a-nity
/. There is a slo( termination of the response0slo( dissociation rate
iv. Endocrine cells secrete many ligands 2 thus thetarget cells must be speci,c (ith a high a-nity
v. E3ample: Steroids
b. Synaptic Signaling echanism:i. Signaling is 45ST
1. +ses electrical impulses over short distanceii. Signals reach high local concentrations
1. %eceptors have lo( a-nity for the signala. echanically based 0based on the
placement of the synapses/. There is a rapid termination of the response
06uic7 dissociation rateiii. Secrete fe( distinct ligands 2 the speci,city comes
from the precise nerve8target cell contact point
iv. E3amples: Peptides and proteins9 catecholamines
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Principles of Signal Transduction: Objectives
/. Be able to identify the four major types of signal transductionpath(ays and give e3amples of ligands and cellular responsesfor each.
a. %eceptor Tyrosine inasei. #igands: *nsulin" lots of gro(th factors
ii. *nsulin %eceptor Signaling:1. %eceptor binds t(o signal compounds 0in this
case" insulin peptide (hich activates atyrosine auto7inase. This also phosphorylates*%S;1 0ro(th: *%S1 phosphorylates Shp" activating
%as.a. %as activates 5P (hich activates
Transcription factors (hich promotegro(th
/. >lucose +pta7ea. *%S;1 phosphorylates P1?" initiating a
phosphorylation cascadei. #eads to >#+T@ 0transporters of
glucose onto the plasmamembrane
?. >lycogen )eposistiona. *%S1 phosphorylates P1?" initiating a
phosporylation cascadei. #eads to stimulation of enAymatic
steps in the conversion of glucose
to glycogenb. > Protein;#in7ed %eceptors
i. #igands: a great variety use > Protein;#in7ed%eceptors
1. atecholamines" Ts" Peptide hormonesCii. / possible cellular responses:
1. c5P Signal Path(aya. c5P activates c5P;dependent Protein
inase 0P5 by phosphorylating P5i. inase is a tetramer
1. / c5P;binding chains
/. / catalytic chainsb. Binding causes release of activated
catalytic subunitsc. atalytic units phosphorylate substrates
0usually enAymesd. oderation or reversal of response is
achieved via:i. )ephosphorylation of substrates
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Principles of Signal Transduction: Objectives
1. By phosphatasesii. )egradation of c5P
1. By phosphodiesterases 0P)E
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Principles of Signal Transduction: Objectives
/. Phosphatidylinositol Path(aya. !ormone signal causes increase in
cytosolic aDD and activation of P"leading to / distinct 0but interactingchain of events:
i. aDD binds to almodulin 0a1. yosin #ight hain inase
0# phosphorylatesmyosin
a. auses interaction (ithactin and musclecontracts
/. itric O3ide Synthase 0OSii. Protein inase phosphorylates a
variety of enAymes and proteins1. *on channels 0li7e aD8!D
pumpa. Phosphorylation leads
to increase of cellularp! and proliferation
/. 5ctivation of transcriptionfactors controlling genee3pression
c. *ntracellular %eceptors 0steroidsi. E3amples of ligands: >lucocorticoid" mineralcorticoid"
progesterone" estrogen" androgen" vitamin )" thyroidii. Three domains
1. Transcription activation )omaina. %esponsible for interaction promoting
activity by %5 polymerasei. Thus" ommunication (ith Pol
/. )5 Binding )omaina. Site of direct interaction (ith )5 in the
promoter region of genesi. Thus" %ecognition of !ormone
%esponse Elements?. #igand Binding )omain.
a. Site of high;selectivity binding by steroid
hormonesi. Thus" Binding Site
iii. / 5ctivated Steroid %eceptors recruit the !istone5cetyl Transferase 0!5T omple3
1. #eading to acetylation of histonesa. auses )5 to un(ind
i. 5llo(ing the binding of thetranscription apparatus.
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Principles of Signal Transduction: Objectives
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Principles of Signal Transduction: Objectives
d. #igand >ated hannelsi. onverts e3tracellular signals into electrical impulsesii. Occurs bet(een nerves and target cells 0ated channel opens" allo(ing entry of ionsiii. E3ample: icotinic 5cetylchnoline %eceptor:
1. hannel opening re6uires / molecules of ligand/. hannel opens only brie'y
a. loses (hile still ligated?. #igand dissociates" returning channel to resting
state
@. )issociated 5h is hydrolyAed bycholineresterase
?. Be able to identify or describe the 7ey steps and moleculesinvolved in each of the four major path(ays" including structureand location of receptors" /ndmessenger molecules 0includingcalcium and nitric o3ide" e&ector enAymes" and substrates.
a. #igand;>ated hannelsi. ey Steps:
1. erve terminal releases neurotransmittersa. ia fusion of storage vesicles (ith plasma
membrane
/. T binds channels present in synapse region?. >ated channel opens" allo(ing entry of ions
ii. olecules involved:1. eurotransmitters
a. 5h" >5B5" Serotonin" >lutamate">lycineC
iii. Structure of receptors:1. omposed of F transmembrane polypeptides
a. Each chain GFHH 55s and traversesmembrane four 0@ times
/. 1 heli3 of each chain contains polar 55s:
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Principles of Signal Transduction: Objectives
v. /ndmessenger molecules:vi. E&ector EnAymes:
1. holineresterase 0hydrolyAes dissociated 5hvii. Substrates:
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Principles of Signal Transduction: Objectives
b. %eceptor Tyrosine inases:i. ey Steps:
1. #igand binding to the insulin receptor 0*%a. *nduces phosphorylation on tyrosine
residues on the intracellular domain
b. / ligands of insulin peptide are re6uiredfor full activation
ii. olecules involved:1. *nsulin Peptide/. *%S1?. %as 0for 5P 7inase cascade to promote gro(th
factors@. P1? 0is phosphorylated by *%S1" initiates
phosphorylation cascadeiii. Structure of receptors:
1. Single transmembrane alpha heli3
/. E3ample: *nsulina. / beta and / alpha chains 0sul,de bond
connects themb. 5lpha chains: contain hormone;binding
sitec. Beta chains: traverse the membrane and
contain tyrosine 7inase domainiv. #ocation of receptors:
1. On the plasma membrane 0transmembrane/. E3tracellular domain
a. #igand;binding site
?. *ntracellular domaina. Tyrosine 7inase activity
v. /ndmessenger molecules:1. *%S1/. %as0for 5P 7inase cascade to promote gro(th
factors?. P1? 0is phosphorylated by *%S1" initiates
phosphorylation cascadevi. E&ector EnAymes:
1. 5P inase 0activates transcription factors topromote gro(th
vii. Substrates:
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Principles of Signal Transduction: Objectives
c. Steroid 0*ntercellular %eceptors:i. ey Steps:
1. / #igand;ed Steroid %eceptors recruits a co;activator that contains the enAyme"
/. That enAyme leads to acetylation of histones?. The acetylated histones allo( the )5 to
un(ind@. The un(ound )5 allo(s for the binding of
general transcription factors 0such as Pol **ii. olecules involved:
1. S% 0Steroid %eceptor/. !SP?. *P@. o5 omple3F. T5T5 0gene e3pression begins here via %5
transcriptioniii. Structure of receptors:
1. !/ 2 Transcription activation domain 2 )5binding domain 2 #igand binding domain 2OO!
/. %eceptors are al(ays
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Principles of Signal Transduction: Objectives
d. >;Protein #in7ed %eceptorsi. Structure of receptors:
1. enerates @ intracellular and
e3tracellular loops
b. E3tracellular amino terminus:i. #igand binding site
c. *ntracellular loops:i. > Protein *nteractionii. Phosphorylation;mediated
inactivation1. $hen ?rdloop is
phosphorylated" the receptoris inactivated
ii. c5P Signaling:1. ey Steps:
a. !ormone stimulateion causes rapidincrease in c5P
b. 5denylate cyclase cleaves 5TP togenerate c5P and pyrophosphate
i. *%%EE%S*B#E stepc. )egradation of c5P by
phosphodiesterasei. Jields FK;5P
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Principles of Signal Transduction: Objectives
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Principles of Signal Transduction: Objectives
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Principles of Signal Transduction: Objectives
/. olecules involved:a. c5P" P5 0c5P;dependent protein
7inase?. #ocation of receptors:
a. On Plasma membrane
i. 5lpha chain:1. Binds and hydrolyAes >TP/. 5ctivates adenylate cyclase
ii. Beta and >amma chains:1. 5nchors alpha chain to the
cytoplasmic face@. /ndmessenger molecules:
a. yclic 5P 0c5PF. E&ector EnAymes:
a. 5denylate cyclase cleaves 5TP togenerate c5P and pyrophosphate
i. *%%EE%S*B#E stepb. )egradation of c5P by
phosphodiesterasei. Jields FK;5P
L. Substrates:iii. aDD8Phosphoinositide Signal Path(ay:
1. ey Steps:
/. olecules involved:a. am 0almodulin
?. #ocation of receptors:a. Plasma membrane
i. On they cytosolic face@. /ndmessenger molecules:
a. )iacylglycerol 0)5>
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Principles of Signal Transduction: Objectives
b. *nositol Trisphosphate 0*P?c. aDD *on
F. E&ector EnAymes:a. # 0phosphorylates myosin" causing
muscle contraction
b. itric O3ide Synthase 0OSc. Protein inase 0phosphorylates lots of
enAymes and proteinsL. Substrates:
@. Be able to describe the major mechanisms by (hich each signalpath(ays can be inhibited.
a. Tyrosine inase" Steroid" and #igand;>ated hannels:i. )o(n;regulation of ell Surface %eceptorsii. Prolonged hormone e3posure leads to receptor
degradation
iii.b. >;#in7ed
i. *nactivation of receptors via phosphorylation:1. Excess hormone
a. %esults in receptor that can bind
hormone but not activate > protein/. Phosphorylation of serines and threoninesonintracellular loops
?. A-kinase,rst to phosphorylate (hen c5Plevels get too high" follo(ed by BARK
@. 4ully phosphorylated receptor is furtherbloc7ed from > protein by beta arrestin