Second Messenger Systems MECHANISM OF ACTION OF HYDROPHILIC MESSENGERSHydroph!c messengers c"nnot cross the ce!! mem#r"ne$Ths restrcton %orces them nto " &c!"ssc"!& method o% messenger "cton' n"me!y the prod(cton o% ntr"ce!!(!"r second messengers )hch "re respons#!e %or the e%%ects o% the *"ro(s messengers$ Ths second messenger then s respons#!e %or the m"n%est"tons o% "!! o% the e%%ects o% the prm"ry messenger nsde the ce!! n +(eston$C"sc"des h"*e cert"n "d*"nt"ges to nc!(de sgn"! d*ergence' con*ergence "nd "mp!%c"ton$The res(!t"nt !g"nd,receptor comp!e- s co(p!ed to "n en.yme !oc"ted on the ntern"! s(r%"ce o% the ce!! mem#r"ne "nd stm(!"tes the con*erson o% some met"#o!te nto " second messenger$In " !"rge n(m#er o% c"ses' the second messenger "cts #y stm(!"tng or nh#tng proten phosphory!"ton/ dephosphory!"ton c"sc"des$Lg"nd #nds to receptors !oc"ted onthe e-tern"! s(r%"ce o% the p!"sm" mem#r"ne$ Hydroph!c messenger systems0 G1Proten SystemsAs mentoned pre*o(s!y' hydroph!c messenger response systems re+(re " tr"nsd(cton system to tr"ns%er the sgn"! "cross the ce!! mem#r"ne to the cytop!"sm$In m"ny c"ses ths tr"nsd(cton system n*o!*es " mem#er o% " %"m!y o% protens the g("ny! n(c!eotde reg(!"tory protens or G1protens$These protens (ndergo " cyc!c "ct*"ton/n"ct*"ton )hch s contro!!ed' to " cert"n e-tent' #y !g"nd,receptor comp!e-es$ G1protens e-st "s heterotrmers )th "n ' " "nd " s(#(nt$The "nd s(#(nts %orm " st"#!e dmerc comp!e- )h!e the s(#(nt cont"ns " g("ny! n(c!eotde #ndng ste 2%or )hch the %"m!y s n"med3$In the n"ct*e st"te the n(c!eotde #ndng ste s occ(ped #y GDP$ Act*"ton o% the proten re+(res th"t the GDP #e e-ch"nged %or GTP$Ths s "ccomp!shed #y %ormng " trmerc G1proten comp!e- )hch c"n "ssoc"te )th " receptor$4hen the receptor #nds ts !g"nd The dssoc"ton r"te %or GDP %rom the comp!e- s ncre"sed "nd the n(c!eotde !e"*es the #ndng ste$ Snce GTP s present n ce!!s "t m(ch hgher concentr"tons "nd the "%%nty o% the #ndng ste %or " trphosph"te s hgher' GTP #nds to the comp!e-$ 4hen GTP s #o(nd to the n(c!eotde #ndng ste o% the s(#(nt " n(m#er o% ch"nges/e*ents occ(r$ The "%%nty o% receptor %or !g"nd decre"ses 2so !g"nd tends to dssoc"te %rom receptor3'the G1proten sep"r"tes %rom the receptor "nd sp!ts nto "n s(#(nt "nd " dmer' "nd the 1s(#(nt #ecomes &"ct*e&$In ths st"te t c"n nter"ct )th *"ro(s mem#r"ne protens "nd "!ter ther "ct*tes$ The 1s(#(nt "!so possesses "n nherent GTP"se "ct*ty )hch hydro!y.es the GTP to GDP "nd n"ct*"tes the G1proten$Th(s the cyc!e h"s " #(!t1n o%% s)tch$ The 1s(#(nt "nd the dmer e"ch c"n e-ert #o!ogc"! e%%ects$The type o% G1proten "nd the "cton th"t t h"s s determned #y the 1 s(#(nt' "nd the s(#1%"m!es "re n"med #"sed on ther e%%ects on the en.yme "deny!y! cyc!"se )hch prod(ces cAMP' the %rst second messenger dsco*ered$Those G1protens 21s(#(nts3 )hch stm(!"te "deny!y! cyc!"se "re re%erred to "s Gs "nd those th"t nh#t "re re%erred to "s G

)h!e those th"t do nether "re c"!!ed Go$ 5"cter"! To-nsThe dsco*ery o% the G1protens "nd the e!(cd"ton o% ther mech"nsm o% "cton )"s enh"nced #y the o% *"ro(s #"cter"! endo1to-ns on the cyc!e$The t)o most mport"nt o% these "re cho!er" to-n "nd pert(sss to-n$5oth o% these to-ns ADP1r#osy!"te "rgnne resd(es n G1protens "nd "!ter ther "ct*ty$Ths re"cton (ses NAD6 "s the ADP1r#ose donor "nd re!e"ses ncotn"mde$6NH7N6H7NH ProtenNNNNNH7OH OHN6OO1OP OO1OP OOH OHOOH7N6NNNNNH7OH OHOO1OP OO1OP OOH OHONProten NHNH7N6OH7NN6H Cho!er" to-n ADP1r#osy!"tes the 1s(#(nts o% Gs&s "nd "#o!shes the GTP"se "ct*ty o% the s(#(nt' cre"tng " contn("!!y "ct*e Gs$ Pert(sss to-n ADP1r#osy!"tes the 1s(#(nts o% G

&s "nd pre*ents the dssoc"ton o% GDP %rom the n(c!eotde #ndng ste' cre"tng " contn("!!y n"ct*e G

$Th(s' the e%%ect o% ether to-n s to stm(!"te the "ct*ty o% the "deny!y! cyc!"se system n t"rget ce!!s$ Ths system (ses cyc!c AMP "s the second messenger$Adeny!y! Cyc!"se SystemCyc!c AMP s gener"ted #y the en.yme "deny!y! cyc!"se 2AC3' )hch n t(rn s s(#8ected to #oth stm(!"tory "nd nh#tory np(t %rom !g"nd,receptor comp!e-es *" G1protens 2"nd other so(rces3$As mentoned "#o*e' Gs h"s stm(!"tory e%%ects on AC "nd G

h"s nh#tory e%%ects$The "ct*"ton o% the respect*e G1protens s *" t)o c!"sses o% receptors' one )hch "cts on Gs "nd one )hch "cts on G

$ Cyc!c AMP !e*e!s "re "!so contro!!ed #y remo*"! o% the compo(nd #y the en.yme phosphodester"se )hch con*erts the compo(nd to AMP$ The e%%ects o% cAMP n ce!!s "re m"n%est thro(gh the "cton o% p"rtc(!"r proten 9n"ses' proten 9n"se A&s or cAMP1dependent proten 9n"ses 2CADP:&s3$These en.ymes e-st "s hetero1tetr"meres )th t)o reg(!"tory "nd t)o c"t"!ytc s(#(nts$4hen #o(nd together n " comp!e-' the c"t"!ytc s(#(nts "re n"ct*e$ The #ndng o% cAMP to the reg(!"tory s(#(nt re!e"ses the c"t"!ytc s(#(nts )hch "re then %ree to phosphory!"te serne "nd threonne resd(es n t"rget protens "nd "!ter the "ct*ty o% the phosphory!"ted proten$The phosphory!"ted proten s con*erted #"c9 to ts orgn"! st"te #y the "cton o% phosphoproten phosph"t"ses )hch remo*e the phosph"te gro(ps$ Other Ro!es o% DmerA%ter s s re!e"sed %rom the g("ny! n(c!eotde reg(!"tory proten' the rem"nng dmer p!"ys " ro!e n reg(!"tng the "ct*ty o% the receptor n*o!*ed n the sgn"! tr"nsd(cton p"th)"y$ The dmer recr(ts " G proten1co(p!ed receptor 9n"se 2GR:3 to the mem#r"ne The dmer recr(ts " G proten1co(p!ed receptor 9n"se 2GR:3 to the mem#r"ne )hch phosphory!"tes the receptor n +(eston$ The phosphory!"ted receptor #nds "nother proten "rrestn the receptor,"rrestn comp!e- s ntern"!.ed n the mem#r"ne o% "n endocytotc *esc!e' remo*ng t %rom the poo! o% "ct*e receptors 1 desenst."ton$ Once ntern"!.ed' "rrestn dssoc"tes %rom the comp!e-' the receptor s dephosphory!"ted "nd recyc!ed #"c9 to the p!"sm" mem#r"ne n "n "ct*e st"te$ Other "ctons o% dmer05nds to "nd "ct*"tes :6 ch"nne!s5nds to "nd mod(!"tes "ct*ty o% PLC5nds to "nd mod(!"tes "ct*ty o% Adeny!y! Cyc!"seReg(!"tes the MAP1:n"se p"th)"yIs reg(!"ted #y other dmer #ndng protens s(ch "s phosd(cn$ IP;/DAG SystemThe second mport"nt 7nd messenger system th"t (t!.es G1protens n ts tr"nsd(cton mech"nsm s the one th"t prod(ces t)o second messengers (pon stm(!"ton #y hormones$The 7nd messenger prod(cng en.yme s phospho!p"se C$Ths en.yme hydro!y.es phosph"tdy!1nosto!1 #s1phosph"te 2PIP73 to prod(ce nostde trphosph"te 2IP;3 "nd d"cy! g!ycero! 2DAG3$The en.yme s stm(!"ted #y hormones "ctng thro(gh G

protens$The PIP7 th"t s hydro!y.ed s prod(ced #y phosphory!"tng the < "nd = OH1gro(ps o% phosph"tdy! nosto! (sng ATP "s the phosph"te donor$ O% the t)o 7nd messengers prod(ced' one s hydroph!c 1 IP;' "nd one s hydropho#c 1 DAG$The e%%ect o% DAG s to se+(ester proten 9n"se C to the mem#r"ne "nd stm(!"te ts "ct*ty$The e%%ect o% IP; s to stm(!"te C"66 re!e"se %rom ntr"ce!!(!"r stores n the SER "nd mtochondr"$The re!e"sed C"66 h"s " *"rety o% e%%ects one o% )hch s the stm(!"ton o% proten 9n"se C$ Proten 9n"se C s " %"m!y o% ser/thr proten 9n"ses )hch nc!(de mo!ec(!es )hose "ct*tes re+(re stm(!"ton #y DAG "nd C"66 together' #y DAG #y tse!%' '#y C"66 #y tse!%The %rst type s the c!"ssc"! proten 9n"se C' #(t the other three types h"*e #een %o(nd #y predomn"nt!y mo!ec(!"r #o!ogc"! techn+(es' so!"ted "nd ch"r"cter.ed$ or do not re+(re 7nd messenger stm(!"ton$ G"ted 2:63 Ch"nne!sThe !"st G1proten mod(!"ted 7nd messenger system to #e dsc(ssed )!! #e !g"nd1g"ted :6 ch"nne!s' ne(rotr"nsmtter receptors )hch "ct to ncre"se pot"ss(m cond(ct"nce n post syn"ptc ne(rons "ct *" G1protens$ M(!tp!e )"ys th"t ne(rotr"nsmtters e%%ect post syn"ptc ce!!s0There "re ne(rotr"nsmtter receptors )hch "re themse!*es on ch"nne!s 2$e$ the ACh receptor3' there "re on ch"nne!s )hch "re stm(!"ted #y ne(rotr"nsmtter,receptor comp!e-es *" G1protens 2$e$ :6 Ch"nne!s3 "nd there "re ne(rotr"nsmtters )hch "ct thro(gh st"nd"rd 7nd messenger systems 2$e$ "cton o% norepnephrne thro(gh #oth "nd receptors> receptors "re nh#tory to the AC system "nd receptors "re stm(!"tory to the AC system$ Con*ergence "nd D*ergence "t the Receptor/G1Proten Le*e!4hen one consders the G1proten system o*er"!!' one h"s to re"!.e th"t there s no one1to1one re!"tonshp #et)een " p"rtc(!"r G1proten 2or G1 proten type3 "nd " p"rtc(!"r receptor 2or receptor type3$In "ddton' " p"rtc(!"r G1proten c"n nter"ct )th more th"n one mem#r"ne en.yme' "nd th(s e%%ect more th"n one sgn"!ng p"th)"y 2d*ergence3$An e-"mp!e o% ths s the e%%ect o% G&s on the AC "nd the IP;/DAG systems$A G1proten c"n #e stm(!"ted to e-ch"nge ts #o(nd n(c!eotde #y " n(m#er o% hormone,receptor comp!e-es 2con*ergence3' "nd " hormone,receptor comp!e- c"n nter"ct "nd stm(!"te more th"n one G1proten type 2d*ergence3$ Tyrosne Proten :n"se SystemsPerh"ps the most notce"#!e thng "#o(t the tyrosne proten 9n"se 2TP:3 system s th"t there s no ?7nd Messenger?$The system "!so (ses proten 9n"ses to tr"nsmt "nd "mp!%y sgn"!s ntr"ce!!(!"r!y' ho)e*er the 9n"se s p"rt o% receptor$The #ndng o% hormone #y the receptor res(!ts n the "ct*"ton o% the tyrosne proten 9n"se "ct*ty$The 9n"se "ct*ty phosphory!"tes tyrosne resd(es n s(#str"te protens' "ctng n " c!"ssc"! proten 9n"se stm(!"tory p"th)"y' th(s "!terng the prm"ry str(ct(re "nd "ct*ty o% the t"rget protens$In "ddton the T:P "ct*ty "!so cross1"(to1phosphory!"tes the receptor/TP: comp!e-$ Ths "(tophosphory!"ton pro*des " s(r%"ce %or " n(m#er o% protens' cys1 rch protens' to #nd to$ 4hen #o(nd to the mem#r"ne s(r%"ce #y receptor/TP: comp!e-' these protens c"n c"t"!y.e " n(m#er o% re"ctons$Among these protens s phospho!p"se C' )hch !9e other phospho!p"se C' c"t"!y.es the hydro!yss o% PIP7 to ye!d IP; "nd DAG$There%ore' the TP: system s c"p"#!e o% stm(!"tng the second messengers "nd s(#se+(ent p"th)"ys o% the IP;/DAG system$ A second proten )hch #nds to TP:1P s phosphonostde1;19n"se )hch c"t"!y.es the phosphory!"ton' )th ATP "s the phosph"te donor' o% the ;&1OH o% nosto! resd(es n phospho!pds$Ths gener"tes " %"m!y o% ;&1O1P nostdes )hch "ct to stm(!"te the Proten :n"se 5 p"th)"ys Proten :n"se 5Phosphonostde1;1:n"se phosphory!"tes phosph"tdy!1nostdes "t the ;1OH gro(p$Proten :n"se 5 #nds to the PI1;1P %ormedAnd #ecomes "ct*"ted #y phosphory!"tonThe "ct*"te P:5 then phosphory!"tes *"ro(s s(#str"te protens' "!terng ther prm"ry str(ct(re "nd th(s ther %(ncton$ The %n"! proten o% nterest )hch #nds to TP:1P s GR5,Sos )hch s n*o!*ed n the "ct*"ton o% the MAP 9n"se c"sc"de$GR5,Sos "cts on R"s' " g("ny! n(c!eotde reg(!"tory proten$In ts norm"! st"te R"s h"s GDP #o(nd to " g("ny! n(c!eotde #ndng ste$The presence o% GR5,Sos "cce!er"tes 2c"(ses3 the dssoc"ton o% GDP %rom ths ste' th(s "!!o)ng t to #e rep!"ced #y GTP$4th GTP n ts #ndng ste' R"s s "ct*e "nd "ct*"tes the MAP 9n"se c"sc"de$ R"s nter"cts )th "nother proten R"% to %orm "n "ct*e ser/thr proten 9n"se' MAP 9n"se 9n"se 9n"se 2MAP:::3' "ssoc"ted )th the mem#r"ne$The MAP::: stm(!"tes " proten 9n"se c"sc"de' thro(gh MAP:: "nd MAP:' )hch e*ent("!!y phosphory!"tes *"ro(s tr"nscrpton %"ctors 2TF&s3 "nd other protens 2Rs93 )hch "!so phosphory!"te TF&s$ The res(!t"nt TF1P&s stm(!"te the prod(cton o% ne) mRNA )hch n t(rn !e"ds to the prod(cton o% ne) proten "nd "n "!ter"ton o% ce!! "ct*ty "nd/or %(ncton$MAP :n"se C"sc"de @A:1STAT SystemThe Jan(s Kn"se / Sgn"! Tr"nsd(cton Act*"tors o% Tr"nscrpton system s some)h"t sm!"r to the TP:1MAP: system$The #ndng o% !g"nd c"(ses the receptors to dmer.e$@A: #nds to the dmer.ed receptorsAnd phosphory!"tes them STAT #nds to the phosphory!"te receptorsAnd n t(rn s phosphory!"ted #y @A:> ths phosphory!"ton res(!ts n " dmer."ton "nd "ct*"ton o% STAT )hch tr"ns!oc"tes to the n(c!e(s )here t "cts "s " tr"nscrpton %"ctor$ to %orm dmerc comp!e- 2R1II7AL 73 $ Gro)th F"ctor B Smed Systemto %orm " R1II7AL 7AR1I7 comp!e-Ths system s some)h"t sm!"r to the !"st system' ho)e*er there "re t)o receptors n*o!*ed "nd n(mero(s other stes o% mod(!"ton$The system s the m"n mech"nsm #y )hch mem#ers o% the tr"ns%ormng gro)th %"ctor C 2TGFC3 %"m!y o% protens )or9$These nc!(de messengers s(ch "s TGFC' #one morphogenc proten' "nd "ct*n$The !g"nd 2dmer3 nt"!!y #nds to " hgh "%%nty receptor' R1II' Ths comp!e- recr(ts " second' receptor 2R1I3 )hch h"s !o) "%%nty' R1I s then phosphory!"ted #y " proten 9n"se )hch s p"rt o% the R1II mo!ec(!e$The phosyphory!"ted R1I recr(ts on o% " n(m#er o% protens 9no)n "s SMEDDs$Some o% these SMEDDs "re n t(rn phosphory!"ted #y the 9n"se "ct*ty o% R1II$ The phosphory!"ted SMEDDs then dssoc"tesAnd #nds "nother proten SMED1< to %orm " hetero1tetr"mer' SMED1P7ASMED1