akhir dari neuron presynaptic.

The cyclic AMP stimulates phosphorylation of a postsynaptic membrane ion channel protein (IC) via a protein phosphokinase enzyme. AMP siklik meran san fosforilasi protein membran saluran ion postsynaptic (IC) melalui phosphokinase enzim protein. This event opens the ion channel! allo"in ions to move in or out of the cell! resultin in the eneration of electrical si nals! finally producin a ne" nerve impulse. Acara ini membuka saluran ion! yan memun kinkan ion untuk ber erak dalam atau keluar dari sel! sehin a enerasi sinyal listrik! akhirnya men hasilkan impuls saraf baru. The effect is reversed first by a phosphoprotein phosphatase! "hich de#phosphorylates the ion channel! and secondly by a phosphodiesterase "hich inactivates the cyclic AMP. $feknya adalah dibalik pertama oleh fosfatase phosphoprotein! yan de#phosphorylates saluran ion! dan kedua oleh phosphodiesterase yan inactivates AMP siklik. Couplin bet"een % and AC is kno"n to involve uanylnucleotide# bindin protein (&#protein). Couplin antara % dan AC diketahui melibatkan men ikat protein uanylnucleotide (&#protein). 'ee (i . )ihat &ambar. * for details. * untuk rincian.

(i . &ambar. *. *. 'cheme sho"in the couplin inside the postsynaptic membrane bet"een neurotransmitters and adenylate kinase (C) via uanidine nucleotide#bindin protein (&#protein). 'kema menun+ukkan koplin dalam membran postsynaptic antara neurotransmitter dan siklase kinase (C) melalui protein nukleotida#bindin uanidin (&#protein). ,ey- T! neurotransmitter. %! receptor protein. /! uanidine#bindin protein. C! catalytic subunit of adenylate cyclase. ,unci- T! neurotransmitter! %! reseptor protein! /! men ikat protein uanidin. C! subunit katalitik adenilat siklase. 'ubscript 0s0 to / indicates a stimulatory action. subscript 0i0 to / indicates inhibitory action. 0'ubscript0 s / menun+ukkan tindakan stimulasi. subscript 0i0 untuk / menun+ukkan tindakan pen hambatan. The couplin bet"een the three membrane components is sho"n as bein

reversible. ,oplin antara ti a komponen membran ditun+ukkan seba ai reversibel. The bindin of &TP by / enhances the interaction! "hich can result in either stimulation or inhibition of adenylate kinase! as sho"n! dependin on the cate ory of / involved. Pen ikatan &TP oleh / menin katkan interaksi! yan dapat men akibatkan baik stimulasi atau pen hambatan kinase siklase! seperti yan ditun+ukkan! ter antun pada kate ori / yan terlibat. &TP is removed by its hydrolysis. &TP akan dihapus oleh hidrolisis nya. 'ee also (i . )ihat +u a &ambar. 1. 1.

(i . &ambar. 23. 23. The second#messen er concept. The#messen er ,onsep kedua. The phosphoinositide#inositol system. The#inositol sistem phosphoinositide. /eurotransmitter receptor (%)! buried in the post#synaptic membrane! interacts "ith neurotransmitter (T) and initiates formation of inositol (2!4!5) triphosphate (IP 6 )! the second messen er (the first messen er is the neurotransmitter). /eurotransmitter reseptor (%)! dimakamkan di membran post#sinapsis! berinteraksi den an neurotransmitter (T) dan pembentukan inisiat dari inositol (2!4!5) trifosfat (IP 6)! utusan kedua (utusan pertama adalah neurotransmitter). This is achieved by activation of the enzyme phosphoinositidase C (PIC! also in the membrane) via &#proteins "ith the conse7uent hydrolysis of a membrane phospholipid (PI! phosphatidyl inositol (4!5) diphosphate) "hich is located close to the enzyme and is indicated by the black heads. 8al ini dicapai den an aktivasi enzim C phosphoinositidase (PIC! +u a pada membran) melalui &#protein den an hidrolisis akibat dari fosfolipid membran (PI! inositol fosfatidilkolin (4!5) difosfat) yan terletak dekat den an enzim dan ini ditun+ukkan den an kepala hitam. The second messen er! IP 6 ! releases calcium from intracellular stores and thereby raises the level of free calcium in the cytoplasm of that neuron. 9tusan kedua! IP 6! melepaskan kalsium dari toko#toko intraseluler dan den an demikian menin katkan tin kat kalsium bebas dalam sitoplasma neuron itu. This second messen er is inactivated by another enzyme! inositol phosphatase. Ini messen er kedua adalah tidak aktif oleh enzim lain! fosfatase inositol. The other product of PI hydrolysis is di lyceride (:&). Produk lain dari hidrolisis PI adalah di lyceride (:&). This activates the enzyme protein kinase C (P,C)! "hich be ins to phosphorylate various proteins! includin specific ion channels! causin them to open and enerate synaptic potentials and eventually to produce! or block! nerve impulses. Ini

men aktifkan enzim protein kinase C (P,C)! yan mulai phosphorylate berba ai protein! termasuk saluran ion tertentu! menyebabkan mereka untuk membuka dan men hasilkan potensi sinaptik dan akhirnya untuk memproduksi! atau blok! impuls saraf. P,C activity can also influence rates of neurotransmitter release! as "ell as produce profound effects on cell ro"th and development by influencin ene e;pression. aktivitas P,C +u a dapat mempen aruhi tin kat pelepasan neurotransmitter! serta men hasilkan efek mendalam pada pertumbuhan sel dan pen emban an den an mempen aruhi ekspresi en. 4. 4. Neuromodulators Neuromodulators It is now well established that the synaptic action of a neurotransmitter may be modulated (ie made more or less efficient) by a third party, a neuromodulator substance, thereby amplifying or attenuating the action of the neurotransmitter. This seems to be achieved by more than one mechanism. Thus, the neuromodulator has the capacity to enhance or decrease the extent of release of the neurotransmitter following action potential invasion of the nerve terminal. or example, adenosinetriphosphate (!T"), secreted together with the neurotransmitter, will decrease noradrenaline or acetylcholine release from some adrenergic or cholinergic nerves, respectively. In other cases, the neuromodulator will alter the efficiency with which the neurotransmitter interacts with its neuroreceptor so as to allow the inward, or outward, flux of more ions per unit time by# ( a ) lengthening the opening period, ( b ) causing a greater fre$uency of channel opening, or ( c ) causing a greater activation of neuroreceptor%lin&ed en'ymes (eg adenyl cyclase). !nother, rather curious, neuromodulator substance is of considerable interest because of its lin&s with ben'odia'epine anxiolytic (anxiety%reducing) drugs. In fact, the existence of this naturally occurring neuromodulator has been inferred from the potent facilitatory actions of anxiolytic ben'odia'epines, such as dia'epam ((alium), on the most widespread inhibitory neurotransmitter system in the nervous system, namely the )!*! (+%aminobutyric acid) system. These ben'odia'epine drugs both increase the affinity of )!*! for )!*! neuroreceptors located on synaptic membranes, and enhance )!*!%mediated behavioural responses and synaptic potential generation. ,oreover, there are neuroreceptors naturally present in the brain which very specifically bind to the drugs. The endogenous ben'odia'epine receptor protein (or binding site) is thought to form part of the )!*! receptor complex. -hen released from its nerve endings (or co% released with )!*! from )!*!ergic nerve endings) it wor&s by increasing the extent, or time period, of opening of )!*!%operated chloride ion channels ( ig. ..). There has been a thorough hunt in the brain over the past fifteen years for the indwelling (alium%li&e endogenous ben'odia'epine, but with little firm success. (arious candidates have been found, but as yet no endogenous substance has been isolated which completely mirrors the properties of the endogenous neuromodulator, or endo'epine, as it has now been termed. The latest front runner is /0N (octadecaneuropeptide), an .1 amino acid neuropeptide which has most of the properties of (alium. ! specific bloc&ing agent for /0N has been developed, called luma'enil, which prevents the actions of both (alium and /0N supporting the case for /0N as the endogenous ben'odia'epine. ! precise definition of a neuromodulator is difficult to produce, since the same substance may act as a neurotransmitter in one synapse, and a neuroregulator at another synapse. Therefore, a definition must represent the category of neuroactivity at a particular site, rather than the identity of the substance itself. or instance, !T", !0", !," (adenosine tri%, di%, and mono%phosphates), or adenosine itself, may function as a neurotransmitter or as a neuromodulator according to the nature of the neuroreceptors with which it interacts.

(i . &ambar. 22. 22. /eurotransmitter and neuromodulator action. a. a. Model of &A<Aer ic synapse functionin "ith a double si nal eneration! that is &A<A and a neuromodulator "hose actions are mimicked by benzodiazepine an;iolytic dru s such as )ibrium and =alium. The coupler for the &A<A reco nition site and chloride ion (Cl) channel is sho"n as a postsynaptic membrane protein. In b. the &A<A! "hen released alone! is seen to operate the chloride ion channel at normal levels of openin ! allo"in standard rates of Cl influ;. In c. :alam c. the released neuromodulator "orks throu h the receptor! alon "ith &A<A! to increase the influ; of Cl throu h the channel by interactin "ith the &A<A receptor! and chan in its protein shape. 2. 2. 3oexistence and co%release of neurotransmitters The long%held dictum, enunciated by 44 0ale (.562) and later developed by 73 8ccles in the .529s, that :only one and the same neurotransmitter is released by each neuron at all of its nerve terminals, at each of its terminals: (0ale:s principle), is no longer universally tenable. 0i&tum lama dipegang, diucap&an oleh 44 0ale (.562) dan &emudian di&embang&an oleh 73 8ccles pada .529% an, bahwa :hanya satu dan neurotransmitter yang sama dirilis oleh masing%masing neuron di semua terminal saraf tersebut, pada masing%masing terminal: ( "rinsip 0ale), tida& lagi universal dipertahan&an. -e now have many examples where neuroactive peptides coexist with longer% standing (:classical:) neurotransmitters, such as acetylcholine, noradrenaline, serotonin, and )!*!. ;ami se&arang memili&i banya& contoh di mana peptida neuroactive hidup berdampingan dengan lagi%berdiri (:&lasi&:) neurotransmitter, seperti asetil&olin, noradrenalin, serotonin, dan )!*!. The coexistence of other, relatively newly established, neurotransmitters, such as !T" within cholinergic and adrenergic neurones is also now well founded. ;oe&sistensi lainnya, yang relatif baru dibentu&, neurotransmiter, seperti !T" dalam neuron &olinergi& dan adrenergi& <uga se&arang <uga didiri&an. or the most part, the different neurotransmitters appear to be contained in different categories of storage vesicle or granule within the nerve terminals concerned, and can be released independently of one another. =ntu& sebagian besar, neurotransmitter yang berbeda tampa&nya ter&andung dalam berbagai &ategori vesi&ula penyimpanan atau granula dalam terminal saraf yang bersang&utan, dan dapat dilepas&an secara terpisah dari satu sama lain. Thus, (asoactive Intestinal "eptide ((I") coexists with acetylcholine in parasympathetic nerves supplying the cat salivary

gland, each being contained in its own vesicle type. 0engan demi&ian, vasoa&tif usus "eptide ((I") berdampingan dengan asetil&olin pada saraf parasimpatis memaso& &ucing &elen<ar ludah, masing% masing <enis yang ter&andung dalam vesi&el sendiri. 4igh%fre$uency stimulation of the nerve releases (I", whilst low fre$uencies release acetylcholine. re&uensi tinggi stimulasi saraf rilis (I", sedang&an asetil&olin fre&uensi rendah rilis. 8ach neurotransmitter can act as a neuromodulator to influence the extent of release or post%synaptic actions of the other ( ig. .>). ,asing%masing neurotransmiter dapat bertinda& sebagai neuromodulator untu& mempengaruhi ting&at pelepasan atau tinda&an pasca%sinapti& yang lain ()br. .>).

(i . &ambar. 2>. 2>. Co#transmission at a synapse by t"o neurotransmitters. Co#transmisi pada sinaps oleh dua neurotransmitter. This is the saliva secretin subma;illary land in "hich acetylcholine (ACh)! and a neuropeptide neurotransmitter! =IP (vasoactive intestinal peptide)! coe;ist in the parasympathetic nerve terminals supplyin this land. Ini adalah kelen+ar air liur men eluarkan subma;illary di mana asetilkolin (Ac8)! dan neurotransmitter neuropeptida! =IP (peptida usus vasoaktif)! hidup berdampin an di terminal saraf parasimpatik memasok kelen+ar ini. /ote that the ACh and =IP are stored in separate vesicles and can therefore be released at different rates at different nerve impulse fre7uencies to act on the saliva#secretin acinar cells to either increase (?)! or decrease (@)! saliva secretion. Perhatikan bah"a Ac8 dan =IP disimpan di vesikula terpisah dan oleh karena itu bisa dilepas pada tin kat yan berbeda pada frekuensi impuls saraf yan berbeda untuk bertindak atas sel#asinar mensekresi air liur untuk menin katkan baik (?)! atau penurunan (#)! air liur sekresi. They also act on the blood vessels supplyin the land rela;in (@) the smooth muscles of the blood vessel "alls to allo" a reater flo" of blood carryin precursors to the land for saliva synthesis. Mereka +u a bertindak pada pembuluh darah yan menyediakan kelen+ar santai (#) pada otot polos dindin pembuluh darah untuk memun kinkan aliran darah yan lebih besar memba"a prekursor ke kelen+ar untuk sintesis air liur. Cooperation bet"een the t"o neurotransmitters is achieved by selective release of ACh at lo" nerve impulse fre7uencies! and of =IP at hi h nerve impulse fre7uencies. ,er+asama antara dua neurotransmitter dicapai den an rilis selektif Ac8 pada frekuensi impuls saraf yan rendah! dan =IP di frekuensi impuls saraf tin i. The t"o neurotransmitters are also seen actin as neuromodulators mutually influencin the e;tent of one another0s release and postsynaptic action. ,edua neurotransmiter +u a terlihat bertindak seba ai neuromodulators salin mempen aruhi

satu sama lain se+auh rilis dan tindakan postsynaptic. ,ey- (?)! increased effect. (@)! decreased effect. ,ey- (?)! menin kat berlaku. (#)! penurunan efek. ?. ?. "ostsynaptic and presynaptic neuroreceptors "ostsynaptic dan neuroreceptors presynaptic "ostsynaptic neuroreceptors represent the longer established category of neuroreceptor, and provide the conventional feed%forward of electrical and trophic influences of neurone on neurone. neuroreceptors "ostsynaptic merupa&an &ategori lagi mapan neuroreceptor, dan menyedia&an umpan%ma<u &onvensional pengaruh listri& dan trofi& dari neuron pada neuron. The past three decades have seen the discovery of presynaptic neuroreceptors which serve a modulatory function in neurotransmission, being primarily concerned with controlling the e;tent of neurotransmitter release. Tiga de&ade tera&hir telah melihat penemuan neuroreceptors presynaptic yang melayani fungsi modulatory di neurotransmisi, yang terutama ber&aitan dengan mengendali&an tin kat rilis neurotransmiter. These neuroreceptors respond to the principal neurotransmitter released by the nerve%ending concerned (so%called autoregulation), or to the actions of co%released, or extraneous, neurotransmitters or neuromodulators of different identity (so%called heteroregulation), by reducing or :shutting down: the release of that neurotransmitter. Neuroreceptors ini menanggapi neurotransmitter utama yang di&eluar&an oleh (autoregulasi disebut) peduli saraf%a&hir, atau tinda&an co%dirilis, atau asing, neurotransmiter atau neuromodulators identitas yang berbeda (heteroregulation disebut), dengan mengurangi atau : memati&an :pelepasan neurotransmitter itu. This negative%feedbac& action is the more common conse$uence of presynaptic neuroreceptor activation (eg noradrenaline release from heart, spleen, vas deferens, and also centrally in the brain). Tinda&an negatif%umpan bali& merupa&an &onse&uensi lebih umum a&tivasi neuroreceptor presynaptic (misalnya pelepasan noradrenalin dari <antung, limpa, vas deferens, dan <uga pusat di ota&). ! minor category of presynaptic neuroreceptors actually mediate enhancement (positive% feedbac&) of neurotransmitter release. @ebuah &ategori &ecil neuroreceptors presynaptic sebenarnya memediasi pening&atan (positif%feedbac&) pelepasan neurotransmitter. It seems that both negative% and positive%feedbac& control can be exercised in the same synapse at a few particular central and peripheral axonal endings, particularly of adrenergic nerves. Tampa&nya bai&%negatif dan positif% &ontrol umpan bali& dapat dila&sana&an di sinaps yang sama di beberapa !&hiran tertentu a&sonal pusat dan perifer, &hususnya saraf adrenergi&. In this case, integration of their actions is achieved as follows# when low levels of neurotransmitter (eg noradrenaline) are present in the synaptic cleft, the facilitatory (usually beta%type) neuroreceptors are activated, leading to increased release of neurotransmitters. 0alam hal ini, integrasi dari tinda&an mere&a dicapai sebagai beri&ut# &eti&a ting&at rendah neurotransmitter (misalnya noradrenalin) yang hadir di celah sinapti&, (biasanya beta%type) facilitasi neuroreceptors dia&tif&an, yang menyebab&an pening&atan rilis neurotransmiter. -hen higher concentrations are reached in the cleft, the inhibitory (usually alpha% type) adrenoreceptors come into play, resulting in a reduction in the level of noradrenaline release. ;eti&a &onsentrasi yang lebih tinggi yang dicapai dalam celah tersebut, (biasanya alfa%<enis) penghambatan adrenoreseptor i&ut bermain, sehingga mengurangi ting&at pelepasan noradrenalin. Thus, differential sensitivity to neurotransmitter concentration allows a delicate balance to be maintained between the opposing actions of the two categories of pre%synaptic neuroreceptor. 0engan demi&ian, diferensial &epe&aan terhadap &onsentrasi neurotransmitter memung&in&an &eseimbangan yang harus di<aga antara tinda&an yang berlawanan dari dua &ategori neuroreceptor pra%sinapti&. A. A. 4ow are neurotransmitters releasedB *agaimana neurotransmitter dirilisB 3alcium ions are the critical factors in triggering neurotransmitter release from the nerve terminal onto ad<oining neurons, muscles, or glands. Normally these calcium ions are at almost undetectable

levels in nerve terminal cytoplasm (.9,), but rapidly flood into the terminals from the surrounding fluid through special voltage%dependent channels during nerve%terminal depolari'ation caused by invasion by the action potential. 8$ually rapidly, the raised cytosolic levels of calcium are reduced to very low, ineffective, concentrations by fast absorption into mitochondria and endoplasmic reticulum within the terminal, and neurotransmitter release therefore ceases. It has been demonstrated that in neuron%to%neuron communication, neurotransmitters can also be released, in the reverse direction, ie from the dendritic tree of the post%synaptic neurone, onto the incoming pre%synaptic axon terminal, as well as from the axon terminals onto this tree, as classically conceived. They can therefore act as retrograde neurotransmitters, providing feedbac& of information (see below). It may be that neurotransmitters can be released from other regions of the neuronal cell surface, including the unmyelinated regions of axons, and from the cell bodies themselves, though the greater proportion of neurotransmitter is released from the nerve terminals, where it is mostly to be found. -hether neurotransmitter is actually released from these various sites by a single process remains unclear. 3ertainly the traditional view envisages an exocytotic process involving the calcium% triggered fusion of the neurotransmitter%filled synaptic vesicles with the inner side of the nerve terminal wall, resulting in the expulsion of about .,999 molecules (one $uantum) of neurotransmitter into the synaptic cleft from each vesicle. ,any multiples of such $uanta are released as the nerve impulse invades the nerve terminal, and this involves fusion with the nerve terminal membrane and exocytosis by e$uivalent multiples of vesicles. 4owever, the synaptic vesicles involved must already be in contact with the terminal membrane, and ready to release their content, as there is less than >99 microseconds between first entry of calcium through its voltage% dependent channel, and first detectable appearance of neurotransmitter in the cleft. The synaptic vesicles which release the neurotransmitters are positioned on the inside face of the membrane close to the point of influx of calcium through its channels, which span the membrane ( ig .6).

(i . &ambar. 26. 26. /eurotransmitter release by e;ocytosis of synaptic vesicles. a. a. Protein domain structure of synaptota min and the other proteins involved in dockin the synaptic vesicles at the presynaptic nerve terminal membrane. b. b. The interrelations of the proteins sho"n in (a) after dockin and before the final e;ocytosis sta e "hich releases the neurotransmitter into the synaptic cleft. Adapted from (i . :iadaptasi dari &ambar. 2 in )ittleton and <ellen (2**5). The balance of evidence is in favour of the vesicular release hypothesis, though this may not be exclusive, and vesicular release, and release by controlled outward diffusion through membrane channels, could be occurring, according to the neurotransmitter in $uestion. The structure and function of the protein molecules present in the membrane or the vesicle, and which are involved in the exocytosis of synaptic vesicles, have been well defined over the past decade. !t least eight of these have been isolated ( ig .6). irst, synaptic vesicles attached, via proteins called neurophysins, to structural cytos&eleton scaffolding (microtubules and microfilaments) to limit their migration, are dissociated from this lin&age by the addition of phosphate groups to the neurophysins by a calcium%stimulated phosphorylating en'yme. The vesicles can now move, slowly, but freely. Then, synaptic vesicles, full of neurotransmitter, are recruited, from those in the immediate vicinity of the pre%synaptic membrane, transported to this membrane, and then doc&ed by attachment close to where an N%type voltage%dependent calcium channel protrudes through the membrane. Then the vesicle is :primed: by addition of a molecule of magnesium%!T" salt complex, to enable it to exocytose to the outside and expel its .,999 molecules of neurotransmitter into the synaptic cleft. The proteins involved here are &nown to include syntaxin and snap%>2 (in the nerve terminal membrane), and synaptotagmin (a calcium%sensing protein), Cab6a and synaptobrevin

((!,") (in the synaptic vesicle membrane). The next, and critical step, is the coming together and fusion of the vesicle%associated proteins with the membrane%associate proteins, rather li&e the fingers of two hands being closely intermeshed ( ig .6). This formation is &nown as the @N!C8 complex (ie @oluble N%sensitive factor !ttachment protein C8ceptor), which is the last stage before neurotransmitter release. It drives vesicle fusion with the terminal membrane and immediate exocytosis by a process called zipperin , in which calcium ions, flooding into the terminal through their membrane channels, bind to synaptotagmin and neurexin to change their conformations. This enables the latter to form the @N!C8, and the former to bind it closer to the calcium channel. /ther proteins, including alpha%snap, Cop, Cab6a, and N@ ( ig. .6) are necessary for doc&ing of the vesicle at the terminal membrane before triggering of tight 'ippering of the @N!C8 proteins. This is followed immediately by exocytosis, with conse$uent neurotransmitter release. @pontaneous exocytosis in the absence of nerve impulse traffic is limited in rate by the vesicle membrane protein, synaptotagmin, whose bloc& is neutrali'ed when it binds to the calcium influxing during nerve impulse traffic. It is interesting that many of these proteins are also found in to be involved in membrane fusion and exocytosis which occurs in invertebrates and even yeasts, indicating their conservation throughout evolution due to their efficacy in these processes. ,ost excitatory glutamate receptors are silent most of the time. )lutamate is the most widely used excitatory neurotransmitter in the central nervous system, and operates far more synapses in the brain and spinal cord than any other neurotransmitter. Det, its most common form, the N,0! ionotropic receptor, is paradoxically silent most of the time and glutamate cannot wor& as a neurotransmitter via these ma<ority receptorsE This is due to its ion channel, which runs across the post%synaptic membrane, being physically bloc&ed by the entry of positively charged magnesium ions which are drawn into the ion channel from the extracellular fluid by the attracting influence of the negative interior of the neurone. This is established by the prevailing negative membrane potential across the neuronal membrane (approx. FA9m(). =ntil this magnesium bloc& is removed by a fall in membrane potential to F49m( or less, the N,0! receptor remains inactive. ,embrane potential depolari'ation, and therefore activation of the N,0! receptor, is achieved by an unusual arrangement in the post%synaptic membrane. This involves the close <uxtaposition of the N,0! receptor proteins with other types of glutamate receptors which are not bloc&ed, such as ionotropic !,"! receptors or metabotropic glutamate receptors (m)luCs). Thus, when glutamate is released into the synaptic cleft from the pre%synaptic terminal, it cannot activate the N,0! receptors, but can activate the other, neighbouring, glutamate receptors. !s a result, the post%synaptic membrane potential is locally depolari'ed by excitatory%postsynaptic potentials (8"@"s# usually due to sodium and calcium influx through the !,"! receptor ion channel). This depolari'ation causes efflux of the magnesium ions bloc&ing the N,0! receptor channel, and this N,0! glutamate receptor can then respond to the synaptically released glutamate neurotransmitter, alongside the !,"! receptors in the same membrane, once sufficient membrane depolari'ation has occurred ( ig. .4). This functional arrangement means that N,0! receptors will only be recruited during periods of high and persistent neural activity, when glutamate release into the synaptic cleft occurs at a high rate. /nce recruited, N,0! receptor activity, which has a large excitatory impact due to the high rate of entry of sodiumGcalcium ions, will massively boost the effect of the glutamatergic excitatory pathway. This occurs as part of the normal way of providing the upper range of intensity of normal nerve impulse traffic, and it is also involved in abnormal situations such as the initiation and propagation of epileptic fits. Cetrograde and gaseous neurotransmitters, and synapses wor&ing bac&wards to establish memory stores. !mong the interesting new discoveries in recent years has been the discovery that communication between nerve cells across a synapse can be two%way, ie forward directed (anterograde), and also retrograde in direction, bac& across the synapse. It was long thought that nerve impulses, when they invaded the nerve terminal, released neurotransmitter by causing influx of calcium ions, and the released neurotransmitter then activated specific postsynaptic receptors on the next neurone in the chain, causing post%synaptic electrical impulses

which stimulated this receiving neurone. It was not conceived that events could ta&e place inside this receiving (postsynaptic) neuron which could result in a retrograde action on the presynaptic neuron which had released the neurotransmitter. It did not seem possible, as no mechanisms for such retrograde action were &nown. This has turned out to be wrongH it is possible, and indeed, common. The thin&ing began to change when two observations were brought together. The first finding, in the .5A9s, was that glutamate%operated synapses, in particular, can somehow learn when they receive an invasion, via the incoming axon, of high%fre$uency (tetanic) nerve impulses I a &ind of intensive bout of neural activity, ie strong synaptic stimulation. This was shown by ma&ing simple electrical recordings from glutamate%operated pathways in isolated slices of the hippocampus, a brain region much involved in memory processes. It has subse$uently been demonstrated to occur in synapses located in other brain regions concerned with memory, eg the cerebral cortex. Thus, after strong, high%fre$uency, tetanic stimulation, the post%synaptic response to a subse$uent lowGnormal fre$uency stimulation was greatly enhanced. This enhancement of postsynaptic response lasted for at least several hours, and has been shown to last wee&s. Indeed, the phenomenon was appropriately called Jong%Term "otentiation of the postsynaptic response (JT", ig. .4). There is also Jong%Term 0epression (J0") of the 8"@" which can occur in other synapses under similar circumstances. The $uestion was, how could the postsynaptic part of the synapse which was part of the next neurone in the chain apparently influence the presynapse to release more transmitter on all subse$uent occasions that it received a low%fre$uency nerve impulse volley, ie how could it learn B !fter all, there was no &nown method of communication back"ards from the second neuron to the first, ie from the postsynapse to the presynapse. The synaptic pathway was thought to be a rectifier, and allow only one%way traffic of the stimulus. It has since been established that there is a parallel increase in the pre%synaptic release of the excitatory neurotransmitter, glutamate, which occurs during the establishment of the JT". ,oreover, JT" was prevented by agents (antagonists) which bloc&ed the synaptic action of glutamate at its post% synaptic receptors, showing that these receptors were somehow involved in JT".

(i . &ambar. 24. 24. Theories of ho" the retro rade aseous neurotransmitter nitric o;ide could be involved in )on #Term Potentiation ()TP) of a lutamater ic hippocampal synapse. Teori ba aimana neurotransmitter nitric oksida retro rade as bisa terlibat di )on #Term potensiasi ()TP) dari sinaps hippocampal lutamater ic. The e;citatory neurotransmitter lutamate first activates AMPA and metabotropic lutamate receptors "hich leads to recruitment of /M:A

receptor activity. /eurotransmiter lutamat ran san pertama AMPA men aktifkan dan reseptor lutamat metabotropic yan men arah ke perekrutan aktivitas reseptor /M:A. Calcium ion entry! via /M:A receptor channels! into the postsynaptic site activates nitric o;ide synthase (/A'). Ion kalsium masuk! melalui saluran reseptor /M:A! ke situs postsynaptic men aktifkan oksida nitrat sintase (/A'). The nitric o;ide as (/A) produced diffuses to the presynaptic site "here it is absorbed by the haem roup of an /A#sensitive uanylate kinase enzyme "hich tri ers the production of cyclic &MP "hich increases neurotransmitter lutamate release. &as oksida nitrat (/A) yan dihasilkan berdifusi ke situs presynaptic mana ia diserap oleh kelompok hem dari uanylate kinase enzim#sensitif /A yan memicu produksi &MP siklik yan menin katkan pelepasan neurotransmitter lutamat. ,ey- m&lu%! metabotropic lutamate receptors. IP! inositol triphosphate second messen er. P:$! phosphodiesterase! "hich inactivates cyclic &MP. ,uncim&lu%! reseptor lutamat metabotropic. IP! kedua utusan inositol trifosfat. P:P! phosphodiesterase! yan inactivates &MP siklik. Adapted from (i > in 8olscher (2**B). :iadaptasi dari &ambar > di 8olscher (2**B). The second observation, in the .519s and .559s, which was to throw light on the mechanism of retrograde synaptic action, and the mechanism of JT", was the finding that at least two gases are wor&ing as neurotransmitters, namely nitric oxide and carbon monoxide. The latter is, of course, a very poisonous gas when inhaled, and excess nitric oxide will also &ill neuronsE These surprisingly atypical neurotransmitters have properties which would allow them to wor& in a synaptically retrograde fashion, because, as gases, they are able to diffuse in all 6%0 spherical directions, once synthesi'ed and released. =nli&e most other neurotransmitters, there are no storage pools for these gases. They must be synthesi'ed and released when needed. Nitric oxide synthesis occurs both in the pre%and postsynapse. It readily dissolves in, and passes through, cell membranes, which do not, therefore, provide a barrier to its movement in any direction. It turns out that nitric oxide gas is made in significant amounts for a short time in the postsynaptic dendrite by the en'yme nitric oxide synthase (N/@) following the action of glutamate <ointly at its postsynaptic !,"! and N,0! receptors (see :silent glutamate receptors:, above). This is because the ionotropic N,0! receptor channel, once activated following sufficient !,"!%glutamate receptor induced membrane depolari'ation, allows a large influx of calcium ions into the postsynapse, where it stimulates N/@ to produce nitric oxide ( ig. .4). The N/@%en'yme is attached to the postsynaptic density ( igs. > and 6), close to the N,0! glutamate receptor. The released nitric oxide gas then diffuses rapidly and reaches the pre%synaptic nerve terminal where it stimulates the formation of the activating agent cyclic%),", by the en'yme )uanylate cyclase. The amount of glutamate neurotransmitter release is then increased via the action of this cyclic )," ( ig. .4). 8ither the postsynaptic production of nitric oxide (or carbon monoxideH see below) must be constant to maintain the JT", once established, or another, as yet unidentified mechanism is responsible for maintenance of the synapse in a potentiated state which persists for a lengthy period of time that greatly outlasts the period of application of the inducing stimulus. Thus, nitric oxide gas is indeed li&ely to be one of the retrograde chemical signals that stimulate the persistent increased release of glutamate by the presynapse which characteri'es JT". /ther candidates include carbon monoxide, which is produced by the en'yme haem oxygenase, which cleaves haem into carbon monoxide and the protein biliverdin. There are many parallels in the range of neuroactivity and the organi'ation of the carbon monoxide and nitric oxide neurotransmitter systems, both in relation to N,0! receptor activation and to calcium influx. The long chain polyunsaturated fatty acid arachidonic acid is another front%running candidate as a retrograde signalling agent initiating JT". These retrograde messengers, and JT", are li&ely to be involved in the early phase of memory, lasting ten or twenty minutes, and involving ac$uisition and consolidation of the memory. This is where, immediately after ac$uisition, the memory is transformed from an initially unstable state into a stabili'ed store.

The calcium%dependent protein &inase en'yme, &nown as calcium calmodulin%dependent &inase (3a, &inase II) may be also be part of the mechanism which allows persistence and consolidation of the synaptic JT" (ie the memory store) triggered by N,0!%receptor activation. Thus, this 3a, &inase protein is located postsynaptically, in particularly high concentrations (>9K49 per cent) in the postsynaptic densities of glutamatergic synapses ( igs. > and 6). It is therefore in a good location to respond immediately to the cytoplasmic calcium ions flooding in through the activated postsynaptic N,0! receptor channels, following high%fre$uency (tetanic) synaptic stimulation. urthermore, 3a, &inase remains active, phosphorylating its own protein structure (autophosphorylation), as well as that of the <uxtaposed N,0! and !,"! glutamate receptors, which further increases the rate of calcium and sodium ion entry through these receptor channels during subse$uent nerve impulse invasion and synaptic activation. ,etabotropic glutamate receptors and their second messengers such as I" (see igs. .9 and .4) are also involved in JT", though this is not so well understood. This activated synaptic state continues long after the calcium levels have dropped bac& to basal levels. ,oreover, the 3a, &inase en'yme protein has been reported to increase in amount in the postsynaptic dendrite during the tetanic stimulation which establishes JT" of the hippocampal synapse. !lso, more synapses have been reported to develop, ie there is remodelling of the post%synaptic dendrite spine. The 3a, &inase II en'yme can therefore :remember: that the <uxtaposed N,0! receptors have been activated, and the resulting calcium influx has produce phosphorylated 3a, &inase II in the post%synaptic density. The stimulation has also stimulated increased gene%expression of the 3a, &inase II protein of the postsynaptic density, dendrite, and cell body of the postsynaptic neurone over the subse$uent 69 minutes ( ig. .2). These changes could partly explain why there is persistence of an enhanced postsynaptic response to subse$uent pre%synaptic invasion of this potentiated synapse by nerve impulses, ie a &ey part of a the molecular mechanism of establishing memory traces in the brain.

(i . &ambar. 25. 25. Theories of the process of induction of )on #Term Potentiation ()TP). Teori dari proses induksi )on #Term potensiasi ()TP). (rom left to ri ht- /ormal stimulation of the presynaptic (upper) nerve terminal activates only the postsynaptically positioned lutamate#AMPA receptors! the +u;taposed lutamate#/M:A receptors bein sterically blocked by ma nesium ion bindin to and occupyin their ion channels. 'tron repetitive (tetanic) stimulation! or hi h# fre7uency nerve#impulse invasion! of the presynapse activates first AMPA receptors sufficiently to cause a lar e depolarization ($P'P) of the postsynaptic membrane! and conse7uent activation of /M:A receptors by outflo" of the blockin ma nesium channels ions. As a result! sodium ions

enter throu h the channel of the AMPA receptors! and sodium and calcium ions enter throu h the /M:A channel! into the cytoplasm of the postsynaptic dendrite! close to the postsynaptic density. This calcium ion influ; induces )TP by activatin nitric o;ide synthase and CaM kinase II (see te;t). There is evidence that )TP involves! in the lon term- increased presynaptic release of lutamate neurotransmitter! permanent increase in the e;pression and state of activation of CaM kinase II! phosphorylation to activate /M:A and AMPA receptors! as "ell as the increased synaptic response (e 23#fold) to subse7uent normal levels of synaptic stimulation by nerve impulses. Adapted from 'anes and )ichtman (2***)! (i . 2 in Trends in /euroscience ! >CB. The dendritic tree and retrograde neurotransmission. "ohon dendriti& dan neurotransmisi retrograde. It has been demonstrated that neurotransmitters can also be released from the dendritic tree of the neuron as well as from a;on terminals as classically conceived. Indeed, the dendrites show locali'ed accumulations of synaptic vesicles which are characteristic of all neurotransmitter release sites (eg synapses, terminal varicosities). *oth long%established neurotransmitters (eg dopamine, !T"), and neuropeptide neurotransmitters, such as vasopressin and oxytocin (normally &nown only as neurohormones), can be released from the dendrites of neurons at many sites within the 3N@, to act as retrograde signals to modulate incoming synaptic transmission, electrical activity, and, in some cases, to modify the morphology of the surrounding presynaptic neurons. @uch dopamine release has been une$uivocally demonstrated to occur from the dendrites of dopaminergic neurones of the substantia nigra of the brain (see basal ganglia ). The neurotransmitters glutamate and )!*! act as retrograde dendritic synaptic signals for the mitral cells and )!*!ergic axonless granule cells of the olfactory bulb. The dendrites can support an invasion of action potentials spreading, bac&ward and upwards, from the cell body where they are generated. It is these invading action potentials which trigger dendritic neurotransmitter release. Through this mechanism, the neuron cell body can transmit information bac&, from its dendrites, to its neighbouring presynaptic neurons, through the actions of dendritically released neuroactive substances. The gaseous neurotransmitters nitric oxide and carbon monoxide and the long, polyunsaturated fatty acid arachidonic acid are other membrane%permeable neuroactive compounds that are released from neuronal dendrites onto synaptic inputs where they have a ma<or role in synapse formation, and memory establishment. 1. 1. -hy are there so many neurotransmittersB The answer to this $uestion is far from resolved. 3ertainly, subgroups of the 29 or so neurotransmitters (Table .) produce different categories of effect in both $ualitative and $uantitative respects, and many will coexist in different neuronal populations. irst, there is the differential speed of response following receptor activation, with ionotropic being some .9%to 69% fold faster than metabotropic responses. !nother dimension is provided in the variety of second% messenger activation of different cascades of biochemical se$uelae, with particular metabotropic neurotransmitter actions being mediated by one or other second messenger system. urther possibilities for adding to the $ualitative features of the response could come through the range of distances through which the neuroactive compounds exert their influence once released, if they can survive the inactivation processes. This may be >9 nanometres within the synaptic cleft but several millimetres from axonal varicosities or unstructured release points, and of course the concentration of neurotransmitter diminishes rapidly with the distance travelled, and some neuroactive substances will be less efficiently inactivated than others. !ctions ranging over a greater volume of tissue would activate specific neuroreceptors sited on a larger variety of neurone types, producing complex se$uences of neuronal triggering, and therefore a greater spectrum of overall responses (so%called trophic or paracrine actions). 3ontinuous (tonic) release of neurotransmitter (eg from axonal varicosities or dendrites), as opposed to discrete and occasional release, would also provide

a basis for variation in the patterns of activation of targeted neurons due to changes in sensitivity, accommodation, and desensiti'ation of neuroreceptors which ensues during continuous neuroreceptor stimulation. Thus, the large number and the chemical variety of neurotransmitters, together with their tendency to activate anatomically distinct neuronal pathways, often in pairs, and the evidence that they provide many palpable possibilities for variation in response, can be seen to provide a chorus of informational voices, each adding tonal colour or timbre to the final output of the brain and nervous system. (Published >334) (:itampilkan >334) D 8( <radford

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