Erythrocyte acetylcholinesterase is a signaling receptor

Mini Re iew Volume 3 Issue 4 - Janua y 2018 DOI: 10.19080/NAPDD.2018.03.555617 No App o D ug Des De Copy igh © All igh s a e ese ed by Ca lo a Saldanha E y h ocy e Ace ylcholines e ase is a Signaling Recep o Ca lo a Saldanha* and Ana Sil a He dade Ins i u e o Biochemis y, Ins i u e o Molecula Medicine, Facul y o Medicine, Uni e si y o Lisbon, Po ugal Recei ed Da e: Janua y 12, 2018; Published Da e: Janua y 23, 2018 *Co esponding au ho : Ca lo a Saldanha, Ins i u e o Biochemis y, Ins i u e o Molecula Medicine, Facul y o Medicine, Uni e si y o Lisbon, Po ugal, Email: Mini Re iew The need o cha ac e ize he composi ion, s uc u e and unc ion o he ed blood cells (RBCs) memb ane, he p esence o he ace ylcholines e ase (AChE) enzyme, which kine ically esembled he b ain es e ase, bu ma kedly di e en om he cholines e ase ound in se um was e idenced [1]. Human e y h ocy e AChE enzyme ac i i y is he highes one in he mammalian scale [2,3]. The p esence o AChE a away o he neu onal sys em aises ques ions abou i s unc ion beyond he enzyme ac ion. He zand Kaplan in hei e ision pape poin ed ha a e in i o hemolysis, ace ylcholines e ase ac i i y can be eco e ed in he e y h ocy e memb ane [4]. Also he endency o couple ion anspo mechanisms ac oss e y h ocy e memb ane wi h AChE was explo ed wi h ailu e [4]. La e was epo ed AChE enzyme ac i i y as a bioma ke o human ed blood cell aging and o RBC memb ane in eg i y [5,6]. The blood o heal hy humans p esen s a wide a ie y o a g adien scale wi h di e en aged classes om olde o younge e y h ocy es each one showing a iable amoun o RBCs esul ing om i s na u al li e span o 120 days. Du ing his pe iod, exo esicles en iched wi h AChE a e eleased om e y h ocy e memb ane o blood ci cula ion es ing he olde e y h ocy e wi h lowe enzyme ac i i y [5,7,8]. Conside ing gende he human emale has highe AChE enzyme ac i i y han he men ma ched in age [9]. Highe human e y h ocy e AChE enzyme ac i i y we e e i ied in pa ien s wi h glaucoma, essen ial hype ension, and ALS [10]. These pa hologies a e in lamma o y ascula diseases cha ac e ized by high concen a ion in blood o in lamma o y molecules, eac i e oxygen species, and eac i e ni ogen species, [10]. The RBCs AChE enzyme ac i i y da a ob ained in hose abo e men ioned ascula diseases ein o ce he Das`s a emen o e y h ocy e AChE be conside ed a bioma ke o in lamma ion [11]. Das e i ied also, ha in blood samples o in lamma o y diseases, wi h high enzyme ac i i y o e y h ocy e AChE, lowe plasma ace ylcholine (ACh) le els we e ob ained [11]. Ace ylcholine molecule ac ing in he pa asympa he ic sys em and in he neu on muscula junc ion, was conside ed as a neu o ansmi e du ing se e al decades. Fu he was also ecognized also as an an i-in lamma o y agen h ough he in e play be ween immune and neu onal sys ems, he nomina ed “choline gic an i-in lamma o y pa hway” [12-14]. This consis s in he ac i a ion o ad ene gic neu ons in he spleen ha libe a e no - epineph ine nea he T cell capable o sec e e ace ylcholine. This non-neu onal ACh ac s on α7 subuni –con aining nico inic ace ylcholine ecep o s exp essed on mac ophages which a e binding induce supp ession on he syn hesis and on he sec e ion o in lamma o y cy okines. Mac ophages ac as an in e ace be ween he b ain and he immune sys em [15]. The ac i a ion o a e en agus ne e by endo oxin o p o-in lamma o y cy okines s imula es hypo halamic-pi ui a y-ad enal an i- in lamma o y esponses conduc ed by he e e en agus ne e. No App o D ug Des De 3(4): NAPDD.MS.ID.555617 (2018) 001 Abs ac The ace ylcholines e ase (AChE), is an enzyme loca ed in he e y h ocy e memb ane ha mo i a e con inually ques ions, abou i s physiological unc ion. The aim o his mini e iew is highligh he ecep o beha io o AChE in human ed blood cells o chemical signals associa ed wi h ni ic oxide mobiliza ion and e lux om e y h ocy es. Da a om he expe imen al models used a e p esen ed. Consequen ly, key pa icipa i e p o eins in he s eps o he signal ansduc ion pa hways, in dependence o AChE ecep o , a e sugges ed o be u he conside ed as po en ial he apeu ic a ge s. Keywo ds: E y h ocy e; Ace ylcholines e ase; signaling ; Ace ylcholine; Recep o Abb e ia ions: RBCs: Red Blood Cells; AChE: Ace ylcholines e ase; ACh: Ace ylcholine; AC: Adenylyl cyclase; cAMP: cyclic Adenosine Monophospha e (cAMP) How o ci e his a icle: Ca lo a Saldanha and Ana Sil a He dades. E y h ocy e Ace ylcholines e ase is a Signaling Recep o . No App o D ug Des De 2018; 3(4) : 555617 DOI: 10.19080/NAPDD.2018.03.555617. 002 No el App oaches in D ug Designing & De elopmen Back o e y h ocy e memb ane enzyme, AChE has he pa icula i y o be inhibi ed by high concen a ions o ACh meaning by i s own na u al subs a e, [10,16]. So, di e en ypes o enzyme complexes may be p esen ed namely, ac i e, inac i e and less ac i e ones acco ding he amoun o ACh exis en in he expe imen al medium [16,17]. The unusual AChE kine ic beha io a non-neu onal en i onmen and he disco e o ni ic oxide (NO) p oduced in he lumen o abbi ao ic endo helium cells unde he p esence ACh, aised us he ques ion i he e is NO inside e y h ocy es [18]. NO was obse ed, in e y h ocy es wi h added ACh, by luo escence mic oscopy [19]. Human e y h ocy e suspensions, in p esence o ACh, we e loaded wi h he pe meable non luo escen p obe diamino luo esceine-2 diace a e (DAF-2Da). In a e y h ocy e luo escence in ensi y o iazolo luo escein (DAF-2T) was isualized as a esul om he eac ion be ween NO and he 4,5- diamino luo escein. We concluded ha ACh, in a dose-dependen way, is able o induce NO mobiliza ion inside he e y h ocy e [19]. Ace ylcholine is known o be p esen in human blood ci cula ion being p oduced by T lymphocy es and endo helial cells [20]. The ci cula ing ACh induces asodila ion o asocons ic ion in dependence o in eg i y o he endo helium, ia he NO syn hesized and eleased o smoo h muscle [21]. Also he NO eleased om endo helial cells can mo e o he lumen o he essels whe e in he blood ci cula ion is cap u ed by ee hemoglobin o sca enged by e y h ocy e p esen [22]. The e y h ocy e NO-heme-hemoglobin adduc o ni osylhemoglobin is o med a high issues oxygen ension, o example, when deoxygena ed blood en e s in o he ascula bed o pulmona y ci cula ion [23]. A e , NO is ans e ed o he hiol g oup o cys eine β93 o Hb o ming S- ni osohemoglobin (SNOHb) conside ed as a NO ese oi molecule [23]. Low issue oxygen ension is pe cei ed by e y h ocy es wi h occu ence o s uc u al allos e ic ansi ions in SNOHb which a o he ans e o i s NO o he hiol g oup o band 3 p o ein, allowing he NO e lux om e y h ocy es o he capilla ies sp eading hose issues [24]. In in i o s udies wi h e y h ocy es ob ained om heal hy dono s unde he p esence o ACh i was e idenced inc eased o NO e lux, e y h ocy e de o mabili y (EE) and dec eased e y h ocy e agg ega ion and hemoglobin oxygen a ini y [25]. O he in i o s udy wi h blood samples aken om pa ien s wi h ascula diseases such as hype ension, hype choles e olemia and kidney ansplan , showing lowe EE han heal hy pe sons ha was amelio a e by he p esence o ACh [24]. A nega i e associa ion be ween EE alues and NO e lux om e y h ocy es was showed in blood samples o hose pa ien s [26]. The NO e lux measu emen s om e y h ocy es a e based on he ACh signal ansduc ion pa hway h ough he AChE– ACh ac i e enzyme complex ( ac i e con o ma ion), associa ed wi h Gαip o ein, adenylyl cyclase (AC) inhibi ion , band 3 p o ein phospho yla ion by p o ein y osine kinase (PTK), p o ein kinase C (PKC) ac i a ion, phosphodies e ase-3 (PDE3) ac i a ion, and low le el o adenosine iphospha e (cAMP) molecules [17,27-31]. Lowe NO e lux om e y h ocy es we e ob ained in p esence o elnac ine and imolol, which a e s ong and mode a e AChE inhibi o s espec i ely, [27,31,32]. E y h ocy e S-ni osoglu a hione (GSNO) is o he NO ese oi molecule exis ing inside e y h ocy e bu able o be sec e ed by he binding o ACh o imolol o AChE o ming ac i e and less ac i e enzyme complex espec i ely [33]. A a iance GSNO e lux om e y h ocy e is null in absence o AChE subs a e o inhibi o [33]. Meanwhile, inside he e y h ocy es he p esence o he inac i e complex AChE-VM showed highe GSNO concen a ion in ela ion o he ac i e enzyme complex AChE-ACh [27,31]. A opposi e GSNO le els inside e y h ocy es we e lowe in p esence o he less ac i e enzyme complex AChE– imolol han in he case o he ac i e enzyme complex AChE-ACh [33,34]. F om all he da a ob ained in he abo e desc ibed s udies we e idenced ha e y h ocy e AChE beyond i s enzyme ac i i y unc ion as a ecep o o signal molecules able o induce escue o NO e lux om human e y h ocy es and i s mobiliza ion om ese oi molecules. The NO de i a i e molecules inside hem as ni i e, ni a e and pe oxyni i e we e also quan i ied in all men ioned s udies. The key p o ein molecules pa icipan s in he chemical signal ansduc ion mechanism o NO unde AChE ecep o once iden i ied we e submi ed o inhibi o s o ac i a o s in in i o models o hype ib inogenemia [35,36]. The acu e phase p o ein ib inogen binds o RBCs memb ane CD47p o ein pa ne o he Rh mac o-complex which is connec ed o he cy oskele on ia p o ein 4.2, and in e ac s also wi h he majo RBC mac o- -complex band 3 p o ein [37]. The p esence o AChE-ACh and AChE- imolol complexes in RBCs induced he e u n o no mal alues he highe NO e lux ob ained unde high ib inogen concen a ion [35,38-40]. Consequen ly his NO sca enged a oids he inc ease concen a ions o he eac i e ni ogen and oxygen species p esen in in lamma o y condi ions. Remembe ing ha he in lamma o y esponse is sys emically associa ed wi h a iable deg ee o endo helium dys unc ion, high plasma ACh and ib inogen concen a ions, he abo e da a a e is acco dance wi h o he s ha conside ace ylcholine as an i- in lamma o y agen . Ou s udies pe o med in i o wi h animal models o in lamma ion demons a ed he an i-in lamma o y unc ion o ACh [41]. The e y h ocy es ob ained om blood samples o pa ien s wi h open glaucoma e idenced ex- i o highe NO e lux alues, in e nal GSNO le els and AChE enzyme ac i i y alues, han hose assessed in e y h ocy es o heal hy pe sons [34,42]. Wi h hese da a we can unde s and he he apeu ic e icacy o o skolin in glaucoma pa ien s [43]. Fo skolin is AC ac i a o , meaning syn hesis o cAMP le els inside RBCs, ha e e ed he highe NO e lux om e y h ocy es model o hype ib inogenemia [44]. Fib inogen binding o RBCs augmen ed he NO e lux unde lowe le els o cAMP [36]. I will be necessa y o con i m in glaucoma pa ien s unde o skolin he apy whe he no maliza ion o NO How o ci e his a icle: Ca lo a Saldanha and Ana Sil a He dades. E y h ocy e Ace ylcholines e ase is a Signaling Recep o . No App o D ug Des De 2018; 3(4) : 555617 DOI: 10.19080/NAPDD.2018.03.555617. 003 No el App oaches in D ug Designing & De elopmen e lux and lowe ni ogen eac i e species occu [34,44]. Also NO dono s like ni oglyce in ac s in ea men and p e en ion o endo helium dys unc ion [45]. Conclusion In conclusion he p o eins he apeu ic a ge s o con ol he RBCs bioa ailabili y in NO (e lux o sca enge) in in lamma o y ascula disease a e AChE, AC, Gi , PTP , PTK, PKC, PI3K and PD3 . Some ac i a o s and inhibi o s o hose p o eins a e al eady disposal o examples ace ylcholine, elnac ine, imolol, ad enaline, o skolin, alsa an, wo mannin de i a e and ilop os . 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Galassi F, Renie i G, Sodi A, Ucci F, Vannozzi L, e al. (2004) Ni ic oxide p oxies and ocula pe usion p essu e in p ima y open angle glaucoma. B J Oph halmol 88: 757-760. 45. Saldanha C, Lopes de Almeida JP, Sil a-He dade AS (2014) Applica ion o ni ic oxide senso in biomedicine. Biosenso s 4(1): 1-17. You nex submission wi h Junipe Publishe s will each you he below asse s • Quali y Edi o ial se ice • Swi Pee Re iew • Rep in s a ailabili y • E-p in s Se ice • Manusc ip Podcas o con enien unde s anding • Global a ainmen o you esea ch • Manusc ip accessibili y in di e en o ma s ( Pd , E-pub, Full Tex , Audio) • Unceasing cus ome se ice T ack he below URL o one-s ep submission h ps://junipe publishe s.com/online-submission.php This wo k is licensed unde C ea i e Commons A ibu ion 4.0 License DOI: 10.19080/NAPDD.2018.03.555617