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Correspondence: M. �eonelli� �epar�amen�o de �isiolo�ia e Bio��sica� �ns�i�u�o de Ci�ncias Biom�dicas� ��P� �v. Pro�. �ineu Pres�M. �eonelli� �epar�amen�o de �isiolo�ia e Bio��sica� �ns�i�u�o de Ci�ncias Biom�dicas� ��P� �v. Pro�. �ineu Pres��es� 1524� �ala 239� 05508�000 �ão Paulo� �P� Brasil. �ax: +55�11�3091�7426. E�mail: mauroleonelli@yahoo.com.br

Received April 27, 2011. Accepted September 8, 2011. Available online September 23, 2011.

Brazilian Journal o� Medical and Biolo�ical Research Online Provisional Version���N 0100�879X Review

This Provisional P�� corresponds �o �he ar�icle as i� appeared upon accep�ance. �ully �orma��ed P�� and �ull �ex� (HTM�) versions will be made available soon.

TRP channels� ome�a�3 �a��y acids� and oxida�ive s�ress in neurode�enera�ion:

�rom �he cell membrane �o in�racellular cross�linksM. �eonelli� M.�.R. Graciano and �.R.G. Bri��o

�epar�amen�o de �isiolo�ia e Bio��sica� �ns�i�u�o de Ci�ncias Biom�dicas� �niversidade de �ão Paulo� �ão Paulo� �P� Brasil

Abstract

The �ransien� recep�or po�en�ial channels �amily (TRP channels) is a rela�ively new �roup o� ca�ion channels �ha� modula�e a lar�e ran�e o� physiolo�ical mechanisms. �n �he nervous sys�em� �he �unc�ions o� TRP channels have been associa�ed wi�h �hermosensa�ion� pain �ransduc�ion� neuro�ransmi��er release� and redox si�nalin�� amon� o�hers. However� �hey have also been ex�ensively correla�ed wi�h �he pa�ho�enesis o� several inna�e and acquired diseases. On �he o�her hand� �he ome�a�3 polyunsa�ura�ed �a��y acids (n�3 �a��y acids) have also been associa�ed wi�h several processes �ha� seem �o coun�erbalance or to contribute to the function of several TRPs. In this short review, we discuss some of the remarkable new findings in this field. We also review �he possible roles played by n�3 �a��y acids in cell si�nalin� �ha� can bo�h con�rol or be con�rolled by TRP chan�nels in neurode�enera�ive processes� as well as bo�h �he direc� and indirec� ac�ions o� n�3 �a��y acids on TRP channels.

Key words: TRP channels; Calcium; Ome�a�3 �a��y acids; Reac�ive oxy�en species; G�pro�ein coupled recep�ors; Neurode�enera�ion

Introduction

Ca2+ si�nalin� is a ubiqui�ous mechanism in �he con�rol o� cell �unc�ion. Many cellular processes depend on Ca2+ levels or on Ca2+ �ransien�s �or �he con�rol o� enzyme ac�iva�ion� �ene �ranscrip�ion� membrane po�en�ial� and cy�oskele�on remodelin�� amon� o�her processes. These processes� in �urn� are responsible �or neuronal ac�iva�ion and neuro�ransmi���er release� con�rol o� cell proli�era�ion and cell dea�h� hormonal balance� and muscle con�rac�ion (1).

The transient receptor potential channels (TRP channels) comprise a relatively recently identified group of cationic permeable channels� which have dis�inc� Ca2+ selectivity (2). In mammals, the 28 members so far identified of this fam�ily are divided in�o 6 sub�roups in �erms o� pro�ein homolo�y: canonical� TRPC channels; vanilloid� TRPV channels; melas�a�in� TRPM channels; ankyrin� TRP� channels; mucolipins� TRPM� channels� and polycys�ins� TRPP channels (2�3). TRP channels are 6 �ransmembrane�spannin� pro�eins wi�h bo�h amino and carboxy �ails loca�ed on �he in�racel�lular side o� �he membrane. The basic s�ruc�ure o� a pro�o�ypic TRP channel� �he TRPV1 channel� is depic�ed in �i�ure 1. These channels can be di��eren�ially modula�ed by a lar�e number o� s�imuli� includin� downs�ream e��ec�ors o� G�pro�ein�coupled recep�ors� calmodulin� �empera�ure� pro�ons� hydro�en peroxide� deple�ion o� Ca2+ s�ores� ca�ions such as Ca2+ and M�2+� and li�ands� which are �ound in several in�redien�s commonly used in worldwide cuisines� such as

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�arlic� vanilla� red peppers� and cinnamon� and s�ill o�her subs�ances �ha� are used in medicine� such as camphor and eu�enol (4�5). However� jus� a �ew direc� endo�enous modula�ors o� TRP have been reco�nized so �ar� and �hey include some arachidonic acid�derived lipids� such as �he bio�enic amines anandamide and N�arachidonoyldopamine (N���)� and �he lipoxy�enase produc�s 12(�) and 15(�) HPETE and leuko�riene B4 (6). The �unc�ion o� TRP channels can also be controlled by several protein kinases, which in turn modulate the sensitivity and the intracellular traffic of these chan�nels (4�7).

Ca2+ flux through TRP channels located in the plasma membrane and in the membranes of intracellular organelles o� exci�able and non�exci�able cells can promo�e chan�es in in�racellular��ree Ca2+ concen�ra�ions and in �he membrane po�en�ial� which can modula�e �he drivin� �orce �or o�her ions and �or Ca2+ i�sel� (8). �n �he cen�ral nervous sys�em� TRP channels are involved in many physiolo�ical processes� includin� �he developmen� o� neuronal �issue� neuronal sprou�in�� cell communica�ion� micro�lial ac�iva�ion� hydroelec�roly�ic balance� con�rol o� body �empera�ure� and sensory si�nalin� (7).

�n �he cen�ral nervous sys�em� TRP channels can con�ribu�e �o exci�a�ory neuro�ransmi��er release (9)� redox si�nal�in� (10�15)� and modula�ion o� mi�ochondrial Ca2+ levels (16). Normally� �hese �unc�ions o� TRP channels can aid normal cell si�nalin�� bu� �heir excessive mobiliza�ion o� in�racellular pa�hways can exacerba�e �he TRP�linked cascade and may even�ually cause �he loss o� Ca2+ homeos�asis� �ri��erin� cell su��erin� and dea�h (12�17�18). �� is no�ewor�hy �ha�� �o da�e� a� leas� 13 human diseases have been linked �o TRP mu�a�ions (19)� such as mucolipidosis �ype 4� caused by specific mutations in TRPML1 channels (20). Several neuronal deficits and behavioral impairment have also been observed in di��eren� TRP knockou� models (21�22). �ddi�ionally� TRP channel �unc�ion has been associa�ed wi�h �he onse� and �he pro�ression o� several neurode�enera�ive diseases� such as �lzheimer (23)� Parkinson (24�25)� s�roke and hypoxia (11�12)� amon� o�hers. The main mechanisms �ha� underlie �he roles played by TRP channels in disease were recen�ly summarized by Nilius (26).

In this review, we intend to summarize some recent intriguing findings that correlate TRP function with some polyun�sa�ura�ed �a��y acids (P���s)� especially �he ome�a�3 (n�3) �a��y acids. The roles played by n�3 �a��y acids in cell si�nalin� pa�hways �ha� can bo�h con�rol or be con�rolled by TRP channels in neurode�enera�ive processes will be emphasized. �ome pro�ein�lipid in�erac�ions �ha� occur on �he cell membrane and o�her direc� ac�ions o� n�3 �a��y acids on TRP �unc��ion and possible cross��alks �ha� can occur be�ween �heir downs�ream pa�hways will be also discussed.

TRP channels are involved in excitotoxicity and oxidant-induced cell toxicity

A large number of TRP channels permit the influx of large amounts of Ca2+ (8) and mi�h� be involved in exci�o�oxici�y and oxida�ive dama�e in neuronal �issue. Bo�h processes have been ex�ensively correla�ed wi�h �he emer�ence and pro�ression o� a lar�e number o� neurode�enera�ive diseases �ha� share Ca2+ imbalance and consequen� oxida�ive�media�ed neuronal injury as �ri��erin� and main�ainin� processes (27).

Exci�o�oxici�y is known �o cause cell dea�h media�ed by pro�use cy�oplasmic Ca2+ en�ry �hrou�h N�me�hyl���aspar�ic acid (NM��) and non�NM�� �lu�ama�e recep�ors� as well as �hrou�h ���ype vol�a�e��a�ed channels� leadin� �o con�sequen� pro�ease ac�iva�ion and reac�ive oxy�en and ni�ro�en species (RO� and RN�� respec�ively) produc�ion (28). �n�i�exci�o�oxic �herapy is a s�ra�e�y used �or �he �rea�men� o� s�roke in clinical prac�ice� which consis�s o� �he an�a�o�nism o� such channels� bu� which canno� comple�ely abro�a�e neuronal dea�h (29). �� �he onse� o� hypoxia and �lucose depriva�ion� disrup�ion o� mi�ochondrial �unc�ion and deple�ion o� �TP reduces �he synap�ic capabili�y �o con�rol bo�h neuro�ransmi��er release and i�s clearance �rom �he synap�ic cle��� causin� massive ac�iva�ion o� �lu�ama�e recep�ors at first, and therefore desensitizing such receptors (28). The main effects of anti-excitotoxic therapy is observed when treatment is applied during the first minutes after hypoxia, strongly suggesting that glutamate excitotoxicity plays a role in neuronal cell death only in the first minutes after hypoxia and glucose deprivation (29).

The second phase o� cell dea�h �ha� occurs in hypoxia and �lucose depriva�ion seems no� �o depend on �he ac�iva�ion o� amino acid recep�ors (28)� possibly indica�in� �ha� o�her ionic channels mi�h� play a role in �his process. �� was recen�ly shown �ha� Ca2+ conduc�ance �hrou�h TRPM7 is an impor�an� requiremen� �or �ri��erin� neuronal dea�h in oxy�en and �lucose depriva�ion models (12). �n �ac�� bo�h TRPM2 and TRPM7 channels seem �o be involved in neuronal cell dea�h induced by oxida�ive s�ress. These pro�eins �orm Ca2+�permeable channels �ha� are �a�ed by RO� and RN�. TRPM7 blockade reduces cell dea�h in ischemic models. Ca2+ influx through those channels is also responsible for ROS and RN� produc�ion� which posi�ively re�ula�e TRPM7 �unc�ion. These resul�s are par�icularly relevan� because �hey indica�e �ha� RO� and RN� produc�ion induced by TRPM7 curren�s may cause a posi�ive �eedback loop responsible �or �he exacerba�ion o� cell dea�h in prolon�ed hypoxia and �lucose depriva�ion (12).

�n�eres�in�ly� M�2+ homeos�asis may also con�ribu�e �o RO��media�ed TRP si�nalin�. �ree M�2+ or M�2+��TP is able to inhibit TRPM7 channel ion flux (30). It is believed that TRPM7 channels are a main route for Mg2+ influx in the central

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nervous sys�em (31)� whereas M�2+/�TP�dependen� an�ipor�ers media�e �he ex�rusion o� M�2+ in exchan�e �or o�her ions. When �TP is low� �he in�racellular concen�ra�ion o� �ree M�2+ is assumed �o rise (32�33). The rise o� in�racellular M�2+ could �hus inhibi� TRPM7. However� i� is no� ye� known which si�nalin� pa�hway is mos� relevan� �or TRPM7 �unc�ion in vivo� whe�her �ha� media�ed by M�2+ or �he one media�ed by RO�/RN�. �� is possible �ha� normal oxy�en and �lucose level res�ora�ion (reper�usion) would induce �he normal �unc�ionin� o� M�2+/�TP�dependen� pumps� �hus reducin� �he inhibi�ion o� TRPM7 channels caused by M�2+. �ddi�ionally� i� is well documen�ed �ha� reper�usion allows �he increase o� RO� and RN� levels and cell dama�e media�ed by such species� which is mainly due �o severe reduc�ion o� an�ioxidan� de�enses (34)� and a vicious cycle could be �ri��ered by �he ac�iva�ion o� TRPM7 and consequen� RO�/RN� produc�ion due �o Ca2+ overload. ��ren��henin� �his idea� TRPM7 suppression wi�h viral vec�ors bearin� shRN� pro�ec�ed hippocampal C�1 neurons and preserved bo�h cell morpholo�y and �unc�ion a�ains� ischemia�induced cell dea�h (11). There�ore� i� seems clear �ha� TRPM7 channels are involved in RO��media�ed neuronal dea�h.

TRPM2 channel �unc�ion is also con�rolled by oxidan�s. H2O2 a� micromolar concen�ra�ions �ha� does no� cause cell dea�h direc�ly� and �he superoxide donor di�hioni�e caused Ca2+ influx through TRPM2 channels in HEK cells. The reduc��ion o� bo�h �lu�a�hione and �hioredoxin �unc�ion and �he incuba�ion o� �he ni�ric oxide (NO) donor �N�P po�en�ia�ed �he e��ec�s o� H2O2 on Ca2+ influx. Moreover, H2O2 reduced cell viabili�y in a dose�dependen� manner (35). �n neurons� micro�molar H2O2 also ac�iva�ed TRPM2� leadin� �o Ca2+ overload and cell dea�h� and down�re�ula�ion o� TRPM2 wi�h siRN� decreased bo�h Ca2+ influx and cell death elicited by H2O2 (36). �n�eres�in�ly� H2O2 can also elici� TRPM2�media�ed Ca2+ curren�s in micro�lial cells� and previous �P� �rea�men� lar�ely po�en�ia�ed �his e��ec� (37)� indica�in� �ha� �hese recep��ors mi�h� be secondary modula�ors o� micro�lial �unc�ion. TRPM2 curren�s are also �ri��ered by ��P�ribose. Oxida�ive and ni�rosa�ive s�ress can enhance ��P�ribose produc�ion by �he nucleus and by mi�ochondrial me�abolism (38). �n �he �ormer case� oxidan�s can cause �N� dama�e� and �he �N� repair machinery �enera�es ��P�ribose as a by�produc�. �� was recen�ly demons�ra�ed �ha� H2O2 and �he ni�roso�hiol donor N�me�hyl�N’�ni�ro�N�ni�roso�uanidine enhanced ��P�ribose produc�ion� which in �urn also caused TRPM2 Ca2+ influx (10). Taken together, these results indicate that TRPM2 mi�h� be a cell sensor �or redox s�a�us in �he normal and diseased neuronal �issue.

The �unc�ion o� o�her TRP channels such as TRPC3 and TRPC4 can also be �ri��ered by oxida�ive s�ress (14�15). The mechanisms found so far to explain the sensitivity of TRPC channels to oxidants suggest that the final routes that culmina�e in TRPC ac�iva�ion are �he ac�iva�ion o� phospholipase C (P�C) and o� �yrosine kinase recep�ors (RTKs). P�C and i�s downs�ream e��ec�ors can posi�ively modula�e �he �unc�ion o� several TRPCs (5). Pharmacolo�ical inhibi�ion o� P�C prevented TRPC3-mediated cationic flux triggered by oxidants (15). On the other hand, expression, down-regulation and �unc�ional disrup�ion o� �rc kinases also reduce TRPC3 ac�iva�ion. Given �ha� �rc kinases can be ac�iva�ed in oxida�ive condi�ions� i� is a� leas� su��es�ive �ha� RTK si�nalin� could have a role in oxidan��induced TRPC3 �unc�ion.

Ca2+�media�ed NO produc�ion can also ensue as a consequence o� TRP ac�iva�ion. �ome TRP channels can also control or be controlled by NO or NO-dependent signaling. NO can both mediate the nitrosylation of specific cysteine residues (��ni�rosyla�ion) (39) or� a��er i�s reac�ion wi�h o�her RO�� i� can increase �he �enera�ion o� o�her oxidan�s involved in ni�ra�ion (40). Our �roup has s�udied �he par�icipa�ion o� TRPV1 channels and correla�ed recep�ors in re�inal develop�men� and neuronal de�enera�ion �ha� occur a��er op�ic nerve dama�e (13�41�43). �� seems �ha� si�nalin� �hrou�h TRPV1 channels is par�ially responsible �or excessive NO produc�ion and consequen� pro�ein ni�ra�ion in bo�h re�inal neuronal and �lial cells (13). �l�hou�h TRPV1 channels are no� direc�ly involved in acu�e cell dea�h a��er op�ic nerve axo�omy� our resul�s indica�e �ha� �heir �unc�ion collabora�es wi�h �liosis o� Müller cells� which seems �o occur as a resul� o� increased pro�ein ni�ra�ion (13). �no�her mechanism �ha� mi�h� be involved is �ha� �he direc� ac�iva�ion o� TRPV1 recep�ors could �ri��er �lu�ama�e release (9�16�44)� which in �urn could lead �o exci�o�oxici�y.

More research is clearly needed �o elucida�e �he possible par�icipa�ion o� �hese channels in processes in which si�nalin� media�ed by RO� and RN� is associa�ed wi�h neuronal cell dea�h in �he brain� such as s�roke� epilepsy� and �lzheimer’s disease� amon� o�hers. The developmen� o� selec�ive dru�s �o modula�e �hese channels will be cer�ainly o� �rea� value �or �u�ure research and �or clinical �rials.

Direct modulation of TRP channels by n-3 fatty acids

Possible direc� and indirec� in�erac�ions be�ween n�3 �a��y acids and TRP channels are summarized in �i�ure 2. n�3 �a��y acids and �heir deriva�ives can con�rol neuronal exci�abili�y �hrou�h �he modula�ion o� several ionic channels. �n �he las� �ew years� several lines o� evidence have indica�ed �ha� TRP channel �unc�ion can be modula�ed bo�h direc�ly and indirectly by n-3 fatty acids. One of the most important findings in the field was reported by Ahern et al. (45). It was demons�ra�ed �ha� �he n�3 �a��y acids docosahexaenoic acid (�H�) and eicosapen�aenoic acid (EP�) a� physiolo�ical concen�ra�ions have �he abili�y �o evoke small TRPV1 curren�s� which seems �o be dependen� on �he previous sensi�iza�

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�ion o� �he channel by pro�ein kinase C (PKC). �H� also reduced �he vol�a�e dependence �or �he ac�iva�ion o� TRPV1� which could indica�e �ha� �H� can �urn TRPV1 more prone �o open a� physiolo�ical vol�a�es. On �he o�her hand� �hese inves�i�a�ors also �ound �ha� bo�h �H� and EP� can displace [3H]�resini�era�oxin bindin�� while �H�� a� concen�ra�ions �ha� displace almos� 100% o� [3H]�resini�era�oxin bindin�� induced curren�s �ha� can be considered small when compared to those elicited by the vanilloid capsaicin. In fact, α-linolenic acid, EPA, arachidonic acid, and γ-linolenic acid also reduced �he curren� evoked by several vanilloids (45). These resul�s su��es� �ha� �hese n�3 �a��y acids can modula�e TRPV1 di�rec�ly a� �he vanilloid bindin� si�e� or �ha� �hey could allos�erically in�erac� wi�h �he recep�or� �hus inducin� chan�es in �he channel s�ruc�ure �ha� bo�h avoid [3H]�resini�era�oxin bindin� and cause con�orma�ional chan�es responsible �or channel opening. This idea is supported by the recent finding that DHA and other amphiphiles can increase membrane elasticity and can �here�ore modula�e �he �unc�ion o� membrane�embedded channels (46)� which suppor�s �he �eneral idea �ha� �he cellular lipid bilayer can also modula�e pro�ein �unc�ion allos�erically� includin� some ionic channels (47).

These resul�s show clearly �ha� TRPV1 curren�s are modula�ed by several P���s� which seem �o reduce �he abili�y of the vanilloid agonists to induce a large cationic influx. Supporting this idea, it has been demonstrated that α-linolenic acid and o�her n�3 �a��y acids also inhibi�ed �he cold�sensi�ive TRPM8 and TRPV1 channels (48�49). Whe�her �hese e���ec�s are due �o �he ac�ion o� �hese P���s on �he a�onis� bindin� si�e or are due �o con�orma�ional chan�es caused by di��eren� TRP pro�ein in�erac�ions wi�h �he lipid bilayer s�ill requires �ur�her experimen�al e��or�s.

The abili�y o� n�3 P���s �o reduce TRPV1 ac�iva�ion is ex�remely exci�in�� since i� adds ano�her �ype o� in�erac��ion be�ween TRPs and n�3 �a��y acids di��eren� �rom �he classical indirec� rela�ionship �ha� is known �o occur be�ween n�3 �a��y acids and n�6 �a��y acids� arachidonic acid deriva�ives� which include some TRPV1 a�onis�s. �everal TRPV1 li�ands are lipoxy�enase deriva�ives o� arachidonic acid (6). �� seems �ha� n�3 �a��y acids are also able �o compe�e wi�h arachidonic acid as subs�ra�es �or lipoxy�enases and cyclooxy�enases� possibly bein� implica�ed in �he reduc�ion o� �he final production of inflammatory mediators that could activate the TRPV1 channel (50). Despite the fact that these results are confined to TRPV1 channels, they may shed a new light on the research on the physiology of other TRP channels. �everal o�her TRP channels such as TRPV3� TRPV4� and TRP�1 can be modula�ed by arachidonic acid and i�s deriva��ives (51�53)� and �he availabili�y and disposal o� arachidonic acid is essen�ial �or �he produc�ion o� such compounds (54). n�3 �a��y acids can also compe�e wi�h o�her �a��y acids� includin� arachidonic acid� bo�h reducin� �he precursors o� inflammatory mediators and forming diverse diacylglycerol (DAG) compounds (55), which could reduce the activation of several pro�ein kinases �ha� di��eren�ially modula�e �he �unc�ion o� mul�iple TRP channels (7).

Indirect modulation of TRP channels by n-3 fatty acids

Epidemiolo�ical s�udies and animal models have demons�ra�ed �ha� P���s are crucial �or �he normal �unc�ion o� �he brain. �n a�ed ra�s� spa�ial memory and hippocampal lon���erm po�en�ia�ion can be improved wi�h die�ary supplemen�a�tion of arachidonic acid and the memory function of human subjects is significantly improved with PUFA supplementation (56�58). �H� is also essen�ial �or neural developmen� and brain �unc�ion (59)� and is responsible �or �he an�iapop�o�ic e��ec� on neuronal dea�h and �he preven�ion o� ischemic brain dama�e (60�61). �n �his re�ard� �he ac�iva�ion o� P����sensi�ive recep�ors mi�h� have an impor�an� par�icipa�ion in �hese processes.

G�pro�ein�coupled recep�ors (GPCRs)� members o� �he lar�e �amily o� �he seven �ransmembrane domain recep�ors� are known �o play physiolo�ical roles in response �o �ree �a��y acids. GPR40 is a member o� �he sub�amily o� homolo�ous GPCRs �ha� include GPR41 and GPR43. GPR40 was repor�ed �o be pre�eren�ially expressed in human and roden� pancreas and in human brain� and �he li�ands o� GPR40 are medium� and lon��chain �a��y acids� such as oleic� arachidonic and docosahexaenoic acids (62,63). Fatty acids binding to GPR40 activate a heterotrimeric G-protein containing the α subunit o� �he Gq pro�ein� which is known �o s�imula�e P�C ac�ivi�y. This enzyme conver�s phospha�idylinosi�ol 3�5�bisphospha�e �o ��G and inosi�ol �riphospha�e (�P3). ��G is a well�known PKC ac�iva�or and �P3 par�icipa�es in endoplasmic re�iculum Ca2+ ex�rusion. PKC phosphoryla�es a lar�e number o� TRP channels a� mul�iple si�es� and several TRP channels can be sensi�ized by PKC� such as TRPV1� TRPV4 and TRPC1� whereas almos� all o�her TRPC channels� in addi�ion �o TRPM4 and TRPM8� appear �o be desensi�ized by PKC phosphoryla�ion (64�65). �ur�hermore� ��G can modula�e �he �a�in� o� a lar�e number o� TRPCs� whereas �P3�media�ed in�racellular Ca2+ s�ore deple�ion mi�h� ac�iva�e a �ew TRPs (66).

The �unc�ion o� GPR40 in �he nervous sys�em is unknown. GPR40 is expressed in neurons o� �he cerebral cor�ex� hippocampus� amy�dala� hypo�halamus� cerebellum� subs�an�ia ni�ra� pons� medulla oblon�a�a� spinal cord� and �he pi�ui�ary �land. �ur�hermore� GPR40 was de�ec�ed in as�rocy�es o� �he cerebral whi�e ma��er� �he molecular layer and mul�i�orm layer o� �he cerebral cor�ex� and in as�rocy�es wi�hin �he pro�eni�or cell niche� such as �he subven�ricular zone (�VZ) alon� �he an�erior horn o� �he la�eral ven�ricle� and �he sub�ranular zone (�GZ) o� �he hippocampal den�a�e �yrus o� adul� monkeys (67). Endo�helial cells o� �he �GZ express GPR40 (68)� which could represen� an impor�an� elemen� o�

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�he an�io�enic niche� where recrui�men� and subsequen� remodelin� are associa�ed wi�h neuro�enesis. The ubiqui�ous dis�ribu�ion o� �his recep�or in �he prima�e brain su��es�s �ha� �a��y acids mi�h� ac� as ex�racellular si�nalin� molecules �o re�ula�e neuronal �unc�ion.

�ncreased expression o� GPR40 in �he �GZ niche has been demons�ra�ed in �he second week a��er �lobal cerebral ischemia in monkeys (68). �� has been specula�ed �ha� �he pos�ischemic increase o� GPR40 in endo�helial cells and newborn as�rocy�es may be able �o enhance local �H� concen�ra�ion� since only as�rocy�es can syn�hesize �H� in �he nervous sys�em (69). �lso� �H� may �unc�ion as an ex�racellular si�nalin� molecule leadin� �o �he �enera�ion and di��eren�ia�ion o� neural pro�eni�ors and newborn neurons �hrou�h �he up�re�ula�ion and ac�iva�ion o� GPR40 (68). �n �his process� �a��y acid�bindin� pro�eins mi�h� par�icipa�e in �he main�enance o� appropria�e levels o� P���s in �he neuro�enic niche� which are required �or �he pos�ischemic neuro�enesis� con�ribu�in� �o �he proli�era�ion o� neural pro�eni�or cells (70).

�H��induced neuronal di��eren�ia�ion� neuri�e �row�h and branchin� o� adul� ra� s�em cells are all media�ed by a mechanism �ha� involves GPR40 si�nalin� in ra� neural s�em cells (N�C) �rans�ec�ed wi�h �he GPR40 �ene (71). Ca2+ mobiliza�ion induced by �H� in GPR40�expressin� N�C was comple�ely blocked by �he inhibi�ion o� �he �P3 recep�or� an impor�an� elemen� ac�iva�ed by GPR40 si�nalin� (71).

�� is ex�remely in�eres�in� �o no�e �ha� several Gq� and ��G�sensi�ive TRP channels such as TRPCs (5) have also been rela�ed �o �he ex�ension o� neuri�es and �row�h o� neuronal cones (4). However� i� s�ill remains comple�ely obscure i� GPR40 recep�ors can modula�e �he �unc�ion o� TRP channels. �espi�e �he recen� clonin� o� GPR40 and �he �ac� �ha� available da�a in �he li�era�ure on brain GPR40� al�hou�h impor�an�� are s�ill limi�ed� i� seems a� leas� s�ron�ly su��es�ive �ha� some cross�links mi�h� occur. Bo�h GPR40 recep�ors and a lar�e number o� TRP channels are widely expressed in �he cen�ral nervous sys�em� and several subproduc�s o� GPR40 ac�iva�ion are well�known TRP ac�iva�ors. The nex� ques�ion �ha� could be asked �o address �his issue is where and how �hose si�nalin� sys�ems could share �heir �unc�ion in neuronal �issue.

Recent findings also indicate that TRP channel function can be modulated by resolvins. Resolvins from the families “E” and “�” are oxidized produc�s �rom �he n�3 �a��y acids EP� and �H�� respec�ively (72). Resolvin bindin� on GPCRs seems �o be par� o� �he mechanism �ha� underlies �heir ac�ion. The �unc�ion o� resolvins has been ex�ensively associ�ated with cellular protection and cessation of the inflammatory signaling (72). Resolvin D1 reduced the activation of the channels TRPA1, TRPV3 and TRPV4 by specific agonists. However, the most exciting finding was that the blockade of specific GPCR cascades did not disrupt the attenuation of TRP channel activity, thus indicating that resolvin D1 may bind and block �hese TRP channels direc�ly (73). On �he o�her hand� i� was shown �ha� resolvin E1 reduced TRPV1�media�ed glutamate release through its action on the Gαi-protein-coupled receptor ChemR23 (74). These results are extremely challen�in�� �iven �ha� resolvins are lipoxy�enase produc�s as much as several endo�enous li�ands o� TRPV1 recep��ors (6�72).

�ince pre�eren�ial me�aboliza�ion o� n�3 �a��y acids or arachidonic acid by lipoxy�enase seems �o be dependen� on diverse �ac�ors� such as previous ace�yla�ion o� cyclooxy�enase 2 by aspirin or by subs�ra�e disposal (50�72)� any �herapeu�ic a��emp� mus� consider �ha� new dru�s �ha� may al�er subs�ra�e availabili�y� or even classic non�s�eroidal an�i�inflammatories, might modulate directly or indirectly the signaling mediated by n-3 fatty acids in TRP channels.

TRPs can also be good, and n-3 fatty acids can harm

Exis�in� evidence indica�es �ha� no �eneral rule can be applied �o �he �unc�ion o� bo�h n�3 �a��y acids and TRP chan�nels in �he brain. The �unc�ion o� several TRP channels is ex�remely impor�an� �or normal brain developmen� (75) and neuronal survival in �he adul�. �s an example� �he �unc�ion o� TRPC1 channels has been implica�ed in �he survival o� �H��Y5Y human neuroblas�oma cells �rea�ed wi�h MPP+ (24)� a widely used neuro�oxin employed in animal models o� Parkinson’s disease. TRPC1 recep�ors are hi�hly expressed in �he subs�an�ia ni�ra (76)� and �hese resul�s clearly show �ha� �he modula�ion o� Ca2+ influx mediated by those channels might be an interesting pharmacological tool for future s�udies on Parkinson’s disease.

On �he o�her hand� increased produc�ion o� oxidan� and oxidized produc�s by n�3 �a��y acids has been ex�ensively demons�ra�ed in �umors and �umoral cell lines (�or a review� see Re�. 77). n�3 �a��y acids and o�her P���s can al�er mi�ochondrial me�abolism� resul�in� in increased RO� produc�ion and mi�ochondrial respira�ory chain impairmen�� which can ul�ima�ely lead �o �TP deple�ion and ionic imbalance (77). �n �his scenario� cells mi�h� have no �ime �o adap� �o �he new Ca2+ levels (78)� and cell dea�h may even�ually occur. �ur�hermore� �H��enriched die�s were repor�ed �o increase �he enzyma�ic ac�ivi�y o� brain NO syn�hase (79)� which mi�h� con�ribu�e �o TRP channel openin�. �s men�ioned be�ore� NO can also par�icipa�e in �he process o� ��ni�rosyla�ion� which is a physiolo�ical and reversible process con�rolled by NO levels and by �he cellular redox s�a�us� �hus enablin� NO �o modula�e �he �unc�ion o� many pro�eins (39). ��ni�rosy�la�ion has been repor�ed �o modula�e �he �unc�ion o� several TRP channels� and i� seems �ha� ni�rosyla�ion increases

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�he sensi�ivi�y o� �hese channels (80). These �ew examples clearly show �ha� �he in�ermodula�ion o� TRP channels and n�3 �a��y acids is very �ar �rom any �eneraliza�ion� and a par�icular analysis concernin� membrane in�erac�ions� cellular par�iculari�ies� microenvironmen�� and �he �ypes o� TRP channels and P���s� as well as o�her neuro�ransmi��ers and in�erac�in� pa�hways� mus� be cau�iously considered be�ore any analysis.

Conclusions

Considerin� �he resul�s ob�ained �hus �ar� i� seems �ha� n�3 �a��y acids �end �o be neuropro�ec�ive� bu� i� is impossible �o asser� �ha� �hey have only a sin�le and �eneral implica�ion in TRP �unc�ion in �he cen�ral nervous sys�em. �ns�ead� �he above da�a indica�e �ha� n�3 �a��y acids can modula�e TRP a� mul�iple levels. ��� on �he one hand� TRP �unc�ion can be elici�ed by n�3 �a��y acids� on �he o�her hand� some repor�s indica�e �ha� �he evoked curren�s are apparen�ly smaller �han �hose observed wi�h o�her a�onis�s. This indica�es �ha� n�3 �a��y acids may a��enua�e lar�e dispari�ies in Ca2+ flow (i.e., no flow versus large flow), which may essentially be at the root of Ca2+ exci�o�oxici�y. �ur�hermore� microenvironmen�al �ac�ors mus� be �aken in�o accoun� when dealin� wi�h �he possible �herapeu�ics o� n�3 �a��y acids applied �o TRP�involved dys�unc�ions� �iven �ha� neuronal cell popula�ions o� a �iven area mi�h� respond di��eren�ly when �acin� similar dru�s or when exposed to a particular lipid profile. It should also be remembered that tumors and tumoral cell lines, due to several �ac�ors includin� �heir lar�e ener�y and pro�ein syn�hesis demand� are expec�ed �o behave qui�e di��eren�ly when compared �o normal cells. �n conclusion� �he rela�ionship o� TRP channels and n�3 �a��y acids is s�ill �ar �rom bein� com�ple�ely elucida�ed� al�hou�h �he �ew examples shown here are ex�remely encoura�in� �or �u�ure research on �he possible in�erac�ions be�ween TRP channels and n�3 �a��y acids under bo�h physiolo�ical and pa�holo�ical condi�ions.

Acknowledgments

The labora�ory o� �.R.G. Bri��o is suppor�ed by �ran�s �rom ��PE�P and CNPq. M. �eonelli and M.�.R. Graciano are suppor�ed by pos�doc�oral �ellowships �rom ��PE�P.

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NALFigure 1. ��ruc�ure o� �he pro�o�ypical �ransien� recep�or po�en�ial (TRP) channel� TRPV1. The TRPV1 channel is a six transmembrane-spanning protein, and the pore (P, yellow) is formed by the fifth and six�h �ransmembrane domains. �� has �hree ankirin repea�s (pink box) and a Ca2+/calmodulin�in�er�ac�in� si�e (dark blue box) in �he N��erminal endin�. The C��erminal endin� has an in�erac�in� si�e �or phospha�idylinosi�ol 4�5�bisphospha�e (P�P2; oran�e box). �everal residues (�reen circles) can be phosphoryla�ed by bo�h �he pro�ein kinases C and � (PKC and PK�� respec�ively). The vanilloid a�o�nis� si�es (red circles) are loca�ed in in�racellular loops and in �he �our�h �ransmembrane domain. �� is in�eres�in� �o no�e �ha� bo�h hea� and pro�on de�ec�ion are media�ed by specific residues located in ex�racellular pro�ein loops. �dap�ed �rom Re�s. 81�83.

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PROVISIO

NALFigure 2. Presump�ive mechanisms o� ac�ion o� n�3 �a��y acids in TRP channels. A� n�3 �a��y acids can compe�e wi�h arachidonic acid and o�her lipids �or P��2. n�3 �a��y acids can subsequen�ly ac� direc�ly on TRP channels or a��er �heir oxy�ena�ion by lipoxy�enases. B� n�3 �a��y acids can increase membrane elas�ici�y and al�er �he biophysical proper�ies o� TRP channels. C� n�3 �a��y acids could also exert their effects on Gαq-coupled receptors, which in turn activate phospholipase C (PLC), with subsequent DAG and IP3 release. ��G may ac�iva�e several TRP channels and �P3 could promo�e �he deple�ion o� in�racellular Ca2+ s�ores� which may also impac� �he modula�ion o� TRP channels. D, Resolvins may also bind to the Gαi-coupled receptor ChemR23, which can modulate several pathways �ha� modula�e TRP channel �unc�ion. TRP = �ransien� recep�or po�en�ial; P��2 = phospholipase 2; ��G = diacyl�lycerol; �P3 = inosi�ol �riphospha�e.