PHRM 301 (Section: 01) - Pharmacology-I: Assignment on Voltage Gate !

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S"#mitte to Mah#"#"l Ho$"e Shihan Senior %ect"rer

S"#mitte #y Mohsin I#na Amin (I&: '01'-1-(0-00') Sai) *arhan Islam (I&: '01'-1-(0-00+) ,arrin Rashi (I&: '01'-1-(0-0-0) .asmia Ho$"e (I&: '01'-1-(0-0-1)

( /cto#er0 '013 &e1artment o) Pharmacy 2ast 3est 4ni5ersity

VOLTAGE GATED ION CHANNEL Voltage-gate ion channels are a class o) transmem#rane ion channels that are acti5ate #y changes in electrical 1otential i))erence near the channel6 these ty1es o) ion channels are es1ecially critical in ne"rons0 #"t are common in many ty1es o) cells7 SODIUM GATED ION CHANNEL Chemistry So i"m channels consist o) a large 8 s"#"nit that associates 9ith other 1roteins0 s"ch as : s"#"nits7 An 8 s"#"nit )orms the core o) the channel an is )"nctional on its o9n7 3hen the 8 s"#"nit 1rotein is e;1resse #y a cell0 it is a#le to )orm channels that con "ct <a= in a 5oltage-gate 9ay7 .he 8-s"#"nit has )o"r re1eat omains0 la#ele I thro"gh IV0 each containing si; mem#rane-s1anning segments0 la#ele S1 thro"gh S>7 .he highly conser5e S? segment acts as the channel@s 5oltage sensor7 .he region linAing omains III an IV is also im1ortant )or channel )"nction7 .his region 1l"gs the channel a)ter 1rolonge acti5ation0 inacti5ating it7 Figure

*ig: &iagram o) a 5oltage-sensiti5e so i"m channel 8-s"#"nit7 G B glycosylation0 P B 1hos1horylation0 S B ion selecti5ity0 I B inacti5ation7 Positi5e (=) charges in S? are im1ortant )or transmem#rane 5oltage sensing7 Mechanism: Voltage-gate <a= channels can e;ist in any o) three istinct states: eacti5ate (close )0 acti5ate (o1en)0 or inacti5ate (close )7 Ce)ore an action 1otential occ"rs0 the a;onal mem#rane is at its normal resting 1otential0 an <a= channels are in their eacti5ate state7 In res1onse to an electrical c"rrent (in this case0 an action 1otential)0 the acti5ation gates o1en0 allo9ing 1ositi5ely-charge <a= ions to )lo9 into the ne"ron thro"gh the channels0 an ca"sing the 5oltage across the ne"ronal mem#rane to increase7 At the 1eaA o) the action 1otential0 9hen eno"gh <a= has entere the ne"ron an the mem#rane@s 1otential has #ecome high eno"gh0 the <a= channels inacti5ate themsel5es #y closing their inacti5ation gates7 !los"re o) the inacti5ation gate ca"ses <a= )lo9 thro"gh the channel to sto10 9hich in t"rn ca"ses the mem#rane 1otential to sto1 rising7 3hen the mem#rane@s 5oltage #ecomes lo9 eno"gh0 the inacti5ation gate reo1ens an the acti5ation gate closes in a 1rocess calle einacti5ation7 3ith the acti5ation gate

close an the inacti5ation gate o1en0 the <a= channel is once again in its eacti5ate state0 an is rea y to 1artici1ate in another action 1otential7 OTASSIUM GATED ION CHANNEL Chemistry Potassi"m channels ha5e a tetrameric str"ct"re in 9hich )o"r i entical 1rotein s"#"nits associate to )orm a )o"r)ol symmetric (!?) com1le; arrange aro"n a central ion con "cting 1ore (i7e70 a homotetramer)7 Alternati5ely )o"r relate #"t not i entical 1rotein s"#"nits may associate to )orm heterotetrameric com1le;es 9ith 1se" o !? symmetry7 All 1otassi"m channel s"#"nits ha5e a istincti5e 1oreloo1 str"ct"re that lines the to1 o) the 1ore an is res1onsi#le )or 1otassi"m selecti5e 1ermea#ility7 Figure

(a) (#) *ig: a) Potassi"m channel0 str"ct"re in a mem#rane-liAe en5ironment7 !alc"late hy rocar#on #o"n aries o) the li1i #ilayer are in icate #y re an #l"e ots7

#) Mechanism o) action o) Potassi"m channel7 Mechanism *rom crystallogra1hic str"ct"ral st" ies o) a 1otassi"m channel0 ass"ming that this str"ct"re remains intact in the corres1on ing 1lasma mem#rane0 it is 1ossi#le to s"rmise that 9hen a 1otential i))erence is intro "ce o5er the mem#rane0 the associate electromagnetic )iel in "ces a con)ormational change in the 1otassi"m channel7 .he con)ormational change istorts the sha1e o) the channel 1roteins s"))iciently s"ch that the ca5ity0 or channel0 o1ens to a mit ion in)l"; or e))l"; to occ"r across the mem#rane0 o9n its electrochemical gra ient7 .his s"#se$"ently generates an electrical c"rrent s"))icient to e1olariDe the cell mem#rane7

CALCIUM GATED ION CHANNEL Chemistry Voltage- e1en ent calci"m channels are )orme as a com1le; o) se5eral i))erent s"#"nits: 810 8'E0 :1-?0 an F7 .he 81 s"#"nit )orms the ion con "cting 1ore 9hile the associate s"#"nits ha5e se5eral )"nctions incl" ing mo "lation o) gating7 Figure

Mechanism 3hen a smooth m"scle cell is e1olariDe 0 it ca"ses o1ening o) the 5oltage-gate (%-ty1e) calci"m channels7 &e1olariDation may #e #ro"ght a#o"t #y stretching o) the cell0 agonist-#in ing its G 1rotein-co"1le rece1tor (GP!R)0 or a"tonomic ner5o"s system stim"lation7 /1ening o) the %-ty1e calci"m channel ca"ses in)l"; o) e;tracell"lar !a'=0 9hich then #in s calmo "lin7 .he acti5ate calmo "lin molec"le acti5ates myosin light-chain Ainase (M%!G)0 9hich 1hos1horylates the myosin in thicA )ilaments7 Phos1horylate myosin is a#le to )orm cross #ri ges 9ith actin thin )ilaments an the smooth m"scle )i#er (i7e70 cell) contracts 5ia the sli ing )ilament mechanism7

!EFE!ENCES 17&ol1hin A! ('00>)7 HA short history o) 5oltage-gate Pharmacol "#$ (S"11l 1): S->B>'7 calci"m channelsH7 Br J

'% Hall0 ,ohn 27 ('011)7 Guyton and Hall Textbook of Medical Physiology with Student Consult nline !ccess (1'th e 7)7 Phila el1hia: 2lse5ier Sa"n ers7 17 >?7 ISC< +(I-1-?1>0-?-(?-I7 Retrie5e '011-03-''7 37J" *H0 !atterall 3A ('003)7 H/5er5ie9 o) the 5oltage-gate )amilyH7Genome Biol # (3): '0(7 so i"m channel

?7 %i J0 4m SJ0 Mc&onal .V ('00>)7 HVoltage-gate 1otassi"m channels: reg"lation #y accessory s"#"nitsH7 "euroscientist "& (3): 1++B'107