- Email: [email protected]
Metabotropic excitatory amino acid receptors reveal their true colors
TiPS- October1992Wol. 121
365
Metabotropicexcitatoryaminoacid receptors reveal their true colors What, when dropped on the hippocampus, stimulates IP3 production and blocks K+ conductZUWS, spike accommodation, Ca2+ channels and synaptic transmission? Hippocampal enthusiasts will immediately know the correct answer - acetylcholine. Indeed, the muscarinic effects of acetylcholine in the hippocampus are some of the best-studied neumtransmitter actions in the brain’. Stimulation of septal afferents causes acetylcholine release in the hippocampus, where activation of one or more subtypes of muscarinic receptors produce5 a varletY Of cellular effects. However, it may be that all of these ezery also beF?P=&ccee;Y W’dtatOry amino add glutamate. Last Year, TiPS published a serle5 of 13 aMet4 On the neurobidogy of glutamate which culminated in a spedal edition combining all these papers. Having squired this tome, the Interested pharmacOlOgl5t might be surprised (Or di5heartened) to learn thfht there is still m0re t0 know about glutamate. However, many impOrtant que5tions remain unanswered, +artlcularly in relation t0 the ‘metabOtrOpic’ excitatory amino e&d receptor. Most neurotransmit&s u5e two types of receptor. GABA*, 5-HT3 and nifxhic acdykholine receptors m~duce their effect5 bv directlv &ning ion channels.' On thi other hand, GABA,,, !!-HT1, 54-l& and musearlnic acetYlcholine receptors are linked by G proteins to a vuiety of &ector molecules which include ion channel5 and enzymes that generate diffusible second messenger. Glutamate recept0rsareals0knOwntoHtinto these categ0rles (Fig. 1). Kainate/ AMPA and NMDA receptors are &and-g&d ion channel5 that can mediate fret excitatory synaptic transmis5ion. A second type of glutamate receptor, which is G prOt&n linked, has been clearly identified in the brain. Several names have been suggested for this receptor (met&Mropic, met&cWphlc, trans-ACPD, cisACPD) but the term metabohopic receptor is currently used. Stimu-
lation of this receptor leads to activation of phospholipase C and generation of IP, (Refs 2, 3). l-lowever, its phy5iolOgical role has been a complete mystery. Recent studies have started to provide a solution to this pmblem. As with much of the glutamate field, a key to this breakthrough has been an advance in receptor pharmacology. Trans-ACPD is a highly selective agonist at the metabotropic recepto$*45. At reasonable concentrations it does not activate NMDA or kainate/AMPA recep tors, but does stimulate IPa [email protected] and &ted phenomenaz. Other substance5, including glutamate, quisqualate and ibotenate, also activate the metabotropic recepto?. However, because these compounds are also very effective at activating Other types of glutamate receptors (including NMDA and kalnate/ AMPA receptors), it is difficult to attribute any of their effect5 to the activation of metabotmpic receptors without making sure that actions at these other sites are first ruled out. On the other hand, the physiological actions of moderate &.&ent&ms of trans-ACPD can be taken as more or less diagno5tic for activation of the metabotropic reorptor. The major effect traditionally ass~dated with meMOtropic receptor activation has been stimulation of IPs synthesis. This effect has been demonstrated in several parts of the b&r?. It is particularly evident in the cerebellum, where Purklnje cell5 possess very high concentrations of both metabotmpic and IPs recept~&. Cultured ashuc~tes from many regions of the brain have also been shown to contain these receptors in abundan&. In assodation with IPa synthesis, metabotropic receptor agonists have al50 been shown to mobilize Ca2+ from intracellular store5 in neuron5**8 a5m7a9 and oocyk~~~‘~ i; which the receptor has been artificiaUy expressed. Now electmphy5iolOgical results using truns-ACFD have started to indicate that this receptor may play an extremely
important role in mediating synaptic transmission in the brain. Most of these data have been obtained in the hippocampus. Stratton and colleagues demonstrated that frans-ACPD produced slow depolarization of CA1 hippocampal neurons”*‘*. This effect was completeiy resistant to concentrations of CNQX (a potent antagonist at kaiite/AMPA recep&) that EompletelY inhibited the excitatorv effects of AMPA on the same cel&+.The slow depolarization was ass0ciated with bn increase in membrane resistance that seemed to be due to the inhibition of a K+ conductance. Stratton et PI. also made a second important observation. Action potentials in CA1 neuruns are followed by a slow after-hyperp0lariz.ation mediated by a Caz+activated K” conductan& (I,,&. This hYperpOlarization limits the ability of the cell to fire action potentials - an effect known as spike accommOdation. TransACPD also blOcked this slow after-hyperpolarizatron, rendering the neurons more excitable. Similar effects On CA1 pYramidal neumns have recently been reported by Desai and Corm”. Inhibitlon of IAHPwas also observed by Baskys et aL” in dentate granule cells, althOugh these authors used quisqualate as their agonist rather- thair trans-ACF’D. Interestingly, they also showed that the inhibition of 1~“p was not apparent when cell5 were injected with the non-p-table GDP analogue, GD@S, which would Black G pmtein-mediated r7EEE%E%e been extended and refined by Charpak et al. in tw0 Ecent publicatiOn5~J6. These authors used a cultured hipp0campal slice preparation in which they could combine electmphysio~cal recording __.__ with mcesurement of [W’li. Here again, clear effect5 Of mCtabotropic receptor agonists (indudmg buns-ACPDI were noted in the kNQX and &PV, or k~nurenic add, which completely abOlished
NlvIDA recepM& Stimulatl~n of metabotropic recept0m on CA3 pyramidal neurons in this preparation reduced spike PcEommodatlon and depOlarlxed the eelIs
TiPS - October1992[Vol.
366 This was accompanied by an increase in membrane resistance. Charpak et al. demonstrated that these effects were associated with the inhibition of at least two Separate K+ conductances. First, IAHP was inhibited by a mechanism not involving a reduction in Ca” influx. Furthermore, although metabotropic receptor agonists produced transient increases in [Ca’+],, the inhibition of I~ur far outlasted this effect. When using BAFTA-filled electrodes to chelate internal Ca2+, IAHPwas abolished. However, under these circumstances, the authors were still able to observe depolarization. This was due to the inhibition of a second, Ba2+-sensitive K+ conductance. This current could also be blocked by activation of muscarinic receptors on the same cells and appears to correspond to IK(M~a K+ conductance that also helps to limit neuronal excitability. Charpak ct PI. then went on to ask an extremely important auestion. Could these events be produced in the hippocampus by svnaoticallv released elutamate? ?h& stimulated the n&y fiber input to the CA3 region in the presence of blockers of NMDA and kainate/AMPA receptormediated responses. Under these they could still conditions, demonstrate a slow excitatory postsynaptic current (EPSC) that had properties identical to the current activated by metabotropic receptor agonists’s_ Furthermore, activation of the mossy fibers also reduced spike zcommodation in the CA3 neurons. A further interesting effect of fruns-ACPD in the hippocampus has been observed by Baskys and Male&a”. They observed that fruns-ACPD reduced the field EPSP recorded in CA1 neurons after stimulation of the Schaffer coUateral/commissural afferents. This was associated with a reduction in the EPSC recorded under v01tage clamp in the same cells. It seems likely, therefore, that the effect was due to a reduction in glutamate release. Recent work also showed tha: fmns-ACPD reduced GABA release in the CA1 region’4. It is not yet clear how the effects of trans-ACPD in the hippocampus are produced at the moteeular level. However, as with muscarinic actions in this region of the brain, both protein kinase
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C and IPs may play a role in mc diating the inhibition of f,,He and IWM)(Ref. 1). The reduction in evoked glutamate release could involve block of voltage-sensitive Ca2+ channels. This is an effect which haa been observed by some authors’s, although not in the study by Charpak et a!. discussed above. Metabotropic receptor activation may also produce similar effects in other parts of the brain. For example, it has previously been shown that the effects of glutamate applied to the nucleus of the solitary tract are only partially blocked by kynurenate and other ionotropic glutamate receptorantaSonists19. Recent work has demonstratedthat stim~ti~ of the solitary tract produces a Ea2+sensitive, slow depolarization of
:
neurons in the nucleus that is mMb!dbytTil?C+ACPD(S.s.chum et al., unpublished). Fidly, ftlnsACPDalao&p&r&emneumnain thedoreoldanlscpkdnudeusof the rat20, bandreduces glutam& rebe at excitatory synapses in the striat&n Asin&atadatthe f this article, 1 tM duced by Pans-ACPD in the hippocampus w also produced bymwuinicqpnists.lnseved other instences, CM5 effiw of norepinepiuine med&ed by alsdmw+rs have d80 been shown to be dmw. Thus, there appearatokananqiqgroup of ncurotnnanitbr rxq&m that canproduce&wexdtationinthe CNS tbmugh the a8me eharacteristic grou of w events. Thereare J er group0 of recep-
TiPS - October 1991/Vol. 121 tors that are also associated with tropic receptor activation in the particular molecular actions. For CNS. It has been shown that the example, there is the group that EPSP recorded in cerebellar directly activates ion channels Purkinje neurons following acnicotinic, GABA.+ tivation of parallel fibers can be (e.g. SHTJ, glycine), while another group is reduced for a considerable period associated with the G proteinof time by concomitant activation mediated activation of K+ conof the climbing fiber input onto ductances and inhibition of Ca?+ the jdssie ceW. This effect, cakd ‘long-term depression’ (LTD), channels (e.g. GABAs, S-l-IT,, adenosine A,, opiate, a2-adrenoappears to be partly mediated ceptors, etc.). It is comforting to through a metabotropic type of know that the previously enigglutamate recepto-. Digital matic metabotropic receptor actuimaging experiments conducted ally fits so nicely into a known on cerebellar Purkinje cells have pattern of receptor physiology. shown that metabotropic receptor However, further complexity agonists cause Caz+ mobrtization in Purkinje neurons that is parmay be expected for metabotropic ticularly localized to the dendritic receptors. It can be seen that the regions of these cells31a2.As in the effects of tram-ACPD so far identified represent a subgroup of hippocampus, agonists also dethose produced by muscarinic polarize Purldnje cells. However, agonists. We know that there are in this case the mechanism does at least five types of muscarinic not appear to involve inhibition of a K+ current, but may instead receptor. It is quite likely that the different groups of muscarinic involve activation of Na+-Ca2+ effects are the result of activation exchangeu. Further studies supof different receptor subtypes. port a role for metabotropic recepThere are already plenty of inditors in the production of LTD, and cations that there may be several also long-term ptentiation in forms of metabotmpic receptor as the hippocampus Js [see Anwyl, well. For example, the antagonists R. (1991) TiPS, 12,324-3261. AP3 and AP4 blocked glutamateThe various examples discussed and ACPD-induced IPs synthesis’ above clearly suggest that we shall see a large number of reports in and Ca2’ mobilization in some the near future describing a cases=, but not in others=. Interwealth of trans-ACPD effects in estlngly, AP3 bl& none of the many regions of the brain. For the elechophysiologlcal effects of trans-ACPD discus& above1z*16~1s. pharmacologist this is very excitOn the other hand, AP3 does ing news. Thus, even though the pharmacology of NMDA and block hens-ACPD- and glutamatekainate/AMPA receptors has prostimulated IPs production when duced potential therapeutic adbrain mRNA is injected into Xenopus oocyte~“~. However, it vances in a number of key areas, glutamate receptor neuropharmafails to block the effects of quiscology appears to have a lot more qualate in the same eggs”. Furthermore, none of the electromileage in it yet. physiological effects of transRICHARD J. MILLER ACPD discussed above is sensitive to pertussis toxin treatment Departmentof Phanrco/ogicsl ml Physio(where this has been investi/ogicul sciences. Unimrsity of Chicup, 947 gated)‘2,‘8. However, the effects of E. 58th Streer,Chicago. IL 60637. IJSA. metabotropic receptor a onists on lP3 production and Ca 28 mobilizRefmnces ation in neuro&, and oocytes3*” I Nhll, R. A., Maknka, R. C. and Kauer, have sometimes been observed to J. A. (19%)PhwsM. Rev. 70.513465 be blocked by such treatment (or 2 w3ch&pp. D:, Bockaert. J. and Skdeczek, F. (1990) Trrnds Phammol. at least partially blocked). If inSri. 11,506-515 deed multiple forms of G protein3 Masu, M., Tanabe, Y., Tsuchida, K., linked glutamate receptors do Sbi~emoto, R. and Nakanlshi, S. (1991) exist, we should know their identNalnm 349,76&765 ity relatively soon as one member 4 Watkins, ). L, Krogwpard-Larsan. P. md Honor& I’. (1990)TrendsPhwmacot. of the family has already been Sci. 11,25-34 cloned3J5 5 Palmer, E., Monaghan, D. T. and There 6 at least one other relaF;ma&W. (19B9)Eur. 1. Plrarmad. tively well-established electro6 H&g, P. M., Bmdt, 0. S. and Snyder, physiological effect of metabo-
367 S. H. (1990)Science249, @&BB4 7 ComeU-Bell, A. H. and Finkbeiner, s. M. (1991)CCIICakium 12, 185-204 6 Mayer, M. C. and Miller, R. J. (1990) J’rendsPhannacol.Sci. 11.254-260 9 Claum, S. R., Holzwarth. J. and M&r, R. J. (19%)Proc. Nntf Acsd. Sri. USA 87, 345&3&n ---____ 10 Sugiyama, H., Ito. 1. and Hirono, C. (1967)Jwure 325,531+x33 11 Stratton, K. R., Worky, P. F. and Baraban, J. F. (19B9)Eur. J. Phmrmscol. 173,235-237 12 Stratton, K. R, Worky, P. F. and Bar&an, J. F. (1990) Eur. 1. Phamacol. 1!?6.?s?-361
13 Baskys, A., Barokt, A. W. and Carkn, P. C. (1990)Can. J. Physiol. PkmmrcoL 6s. Aii
14 Masai, M. A. and Conn, P. J. (1991) J. Newophysiol. 66,40-52 15 Charpak, S., GZhwikr, B. H.. Dok, Q. and Knbpfel,T. (1990) Nature 347, 765-767 16 Charpak, S. and CThwikr, 8. H. Pmt. R. Sot. Loadon,Ser. B (ii press) 17 Baskys, A. and Male&a, R C. (1991) Eur. J. Pkarmacol.193, Ul-132 18 Lester, R. A. J. and Jahr, C. E. (1990) Ncumn 4.741-749 19 Leone, C. and Gordon, F. J. (1969) J. Phsnnacol. Exp. Ther.250,~963 20 Zban& F. and Galb&r, J. P. (1991) Ncumsci. Len. l25,147-l50 21 Lovinger, 0. M. BrainRes. (in press) 22 Irving. A. J., Schofirld, J. C., Watkins, J. C., Stutter, D. C. and CollingidSr. G. L. (19%) Eur. J. Pkurawol. 186, 23 Murphy, S. N. and Miller, R. J. (1969) Mol. Phorntrcol.35,67l-660 24 Su~yarns, H. (1990) Ncumchem. Inl. 16(Sl). 17 (Abstr.) 25 Houamed, K. M. et rl. (1991)Srience252, 13161321 26 Furuya, S., Ohmori, l-i., Shilpmoto. 7’. and Sugiyama H. (19B9) J. Physiol. (Lotldalt)414,539-548 27 Ito, M. (1969) Anna. Rev. Neumsci. 12, 85-102 28 Ito, M. and Karachot, L. (1990) Nerm Rrpoti l,l29-I32 29 Ito, M. and Karachot.L (1990)Neumsci. Res. s,3lu307 30 Linden, D. I., Dicktnson, M. H.. Smeyne,M. and Connor, J. A. (1991) Neuk 7, El-69 31 Dreessen, J., Kano, M., Llano, I. and Konnerth, A. (1991) Pflrqen Arch.
241(Sl), R12 32 Collingrid~, C. L. and Abbott, A. (1991)TrendsPharmscd. Sci. 12,169-170 33 Kn6pfe1, T. and Staub, C. (199’0 Pfhregers Arch. 24l(Sl), R12 34 Stanton, I? K., Chattarji, S. and Sejnowski, C. (1991)Neumsci’L&t. . 127. 61-66 35 McGuinnass, N., Anwyi, R. and Rowan, hi. (1991)Eur./. Pkamfacol. 197,251~232 36 Cu. Y. and Huang, L-Y. (1991) Neuron 6.777484 37 Miller, R. J. Trends Neumsci. (in pmss) 38 Mar&n, N. V., Zucker, R. 5.. Mush. S. 1. and Adams, P. R. (1991)Neumn 6. 53.i-545
-ACPDz
ins, 311s.cis-l-
N,N,N:h”-tatrssc&rdd
365
Metabotropicexcitatoryaminoacid receptors reveal their true colors What, when dropped on the hippocampus, stimulates IP3 production and blocks K+ conductZUWS, spike accommodation, Ca2+ channels and synaptic transmission? Hippocampal enthusiasts will immediately know the correct answer - acetylcholine. Indeed, the muscarinic effects of acetylcholine in the hippocampus are some of the best-studied neumtransmitter actions in the brain’. Stimulation of septal afferents causes acetylcholine release in the hippocampus, where activation of one or more subtypes of muscarinic receptors produce5 a varletY Of cellular effects. However, it may be that all of these ezery also beF?P=&ccee;Y W’dtatOry amino add glutamate. Last Year, TiPS published a serle5 of 13 aMet4 On the neurobidogy of glutamate which culminated in a spedal edition combining all these papers. Having squired this tome, the Interested pharmacOlOgl5t might be surprised (Or di5heartened) to learn thfht there is still m0re t0 know about glutamate. However, many impOrtant que5tions remain unanswered, +artlcularly in relation t0 the ‘metabOtrOpic’ excitatory amino e&d receptor. Most neurotransmit&s u5e two types of receptor. GABA*, 5-HT3 and nifxhic acdykholine receptors m~duce their effect5 bv directlv &ning ion channels.' On thi other hand, GABA,,, !!-HT1, 54-l& and musearlnic acetYlcholine receptors are linked by G proteins to a vuiety of &ector molecules which include ion channel5 and enzymes that generate diffusible second messenger. Glutamate recept0rsareals0knOwntoHtinto these categ0rles (Fig. 1). Kainate/ AMPA and NMDA receptors are &and-g&d ion channel5 that can mediate fret excitatory synaptic transmis5ion. A second type of glutamate receptor, which is G prOt&n linked, has been clearly identified in the brain. Several names have been suggested for this receptor (met&Mropic, met&cWphlc, trans-ACPD, cisACPD) but the term metabohopic receptor is currently used. Stimu-
lation of this receptor leads to activation of phospholipase C and generation of IP, (Refs 2, 3). l-lowever, its phy5iolOgical role has been a complete mystery. Recent studies have started to provide a solution to this pmblem. As with much of the glutamate field, a key to this breakthrough has been an advance in receptor pharmacology. Trans-ACPD is a highly selective agonist at the metabotropic recepto$*45. At reasonable concentrations it does not activate NMDA or kainate/AMPA recep tors, but does stimulate IPa [email protected] and &ted phenomenaz. Other substance5, including glutamate, quisqualate and ibotenate, also activate the metabotropic recepto?. However, because these compounds are also very effective at activating Other types of glutamate receptors (including NMDA and kalnate/ AMPA receptors), it is difficult to attribute any of their effect5 to the activation of metabotmpic receptors without making sure that actions at these other sites are first ruled out. On the other hand, the physiological actions of moderate &.&ent&ms of trans-ACPD can be taken as more or less diagno5tic for activation of the metabotropic reorptor. The major effect traditionally ass~dated with meMOtropic receptor activation has been stimulation of IPs synthesis. This effect has been demonstrated in several parts of the b&r?. It is particularly evident in the cerebellum, where Purklnje cell5 possess very high concentrations of both metabotmpic and IPs recept~&. Cultured ashuc~tes from many regions of the brain have also been shown to contain these receptors in abundan&. In assodation with IPa synthesis, metabotropic receptor agonists have al50 been shown to mobilize Ca2+ from intracellular store5 in neuron5**8 a5m7a9 and oocyk~~~‘~ i; which the receptor has been artificiaUy expressed. Now electmphy5iolOgical results using truns-ACFD have started to indicate that this receptor may play an extremely
important role in mediating synaptic transmission in the brain. Most of these data have been obtained in the hippocampus. Stratton and colleagues demonstrated that frans-ACPD produced slow depolarization of CA1 hippocampal neurons”*‘*. This effect was completeiy resistant to concentrations of CNQX (a potent antagonist at kaiite/AMPA recep&) that EompletelY inhibited the excitatorv effects of AMPA on the same cel&+.The slow depolarization was ass0ciated with bn increase in membrane resistance that seemed to be due to the inhibition of a K+ conductance. Stratton et PI. also made a second important observation. Action potentials in CA1 neuruns are followed by a slow after-hyperp0lariz.ation mediated by a Caz+activated K” conductan& (I,,&. This hYperpOlarization limits the ability of the cell to fire action potentials - an effect known as spike accommOdation. TransACPD also blOcked this slow after-hyperpolarizatron, rendering the neurons more excitable. Similar effects On CA1 pYramidal neumns have recently been reported by Desai and Corm”. Inhibitlon of IAHPwas also observed by Baskys et aL” in dentate granule cells, althOugh these authors used quisqualate as their agonist rather- thair trans-ACF’D. Interestingly, they also showed that the inhibition of 1~“p was not apparent when cell5 were injected with the non-p-table GDP analogue, GD@S, which would Black G pmtein-mediated r7EEE%E%e been extended and refined by Charpak et al. in tw0 Ecent publicatiOn5~J6. These authors used a cultured hipp0campal slice preparation in which they could combine electmphysio~cal recording __.__ with mcesurement of [W’li. Here again, clear effect5 Of mCtabotropic receptor agonists (indudmg buns-ACPDI were noted in the kNQX and &PV, or k~nurenic add, which completely abOlished
NlvIDA recepM& Stimulatl~n of metabotropic recept0m on CA3 pyramidal neurons in this preparation reduced spike PcEommodatlon and depOlarlxed the eelIs
TiPS - October1992[Vol.
366 This was accompanied by an increase in membrane resistance. Charpak et al. demonstrated that these effects were associated with the inhibition of at least two Separate K+ conductances. First, IAHP was inhibited by a mechanism not involving a reduction in Ca” influx. Furthermore, although metabotropic receptor agonists produced transient increases in [Ca’+],, the inhibition of I~ur far outlasted this effect. When using BAFTA-filled electrodes to chelate internal Ca2+, IAHPwas abolished. However, under these circumstances, the authors were still able to observe depolarization. This was due to the inhibition of a second, Ba2+-sensitive K+ conductance. This current could also be blocked by activation of muscarinic receptors on the same cells and appears to correspond to IK(M~a K+ conductance that also helps to limit neuronal excitability. Charpak ct PI. then went on to ask an extremely important auestion. Could these events be produced in the hippocampus by svnaoticallv released elutamate? ?h& stimulated the n&y fiber input to the CA3 region in the presence of blockers of NMDA and kainate/AMPA receptormediated responses. Under these they could still conditions, demonstrate a slow excitatory postsynaptic current (EPSC) that had properties identical to the current activated by metabotropic receptor agonists’s_ Furthermore, activation of the mossy fibers also reduced spike zcommodation in the CA3 neurons. A further interesting effect of fruns-ACPD in the hippocampus has been observed by Baskys and Male&a”. They observed that fruns-ACPD reduced the field EPSP recorded in CA1 neurons after stimulation of the Schaffer coUateral/commissural afferents. This was associated with a reduction in the EPSC recorded under v01tage clamp in the same cells. It seems likely, therefore, that the effect was due to a reduction in glutamate release. Recent work also showed tha: fmns-ACPD reduced GABA release in the CA1 region’4. It is not yet clear how the effects of trans-ACPD in the hippocampus are produced at the moteeular level. However, as with muscarinic actions in this region of the brain, both protein kinase
I
I
Nat Gas GllJR7
f:
and/or GluR3
1
r”“’
T
r
mw,”
c
”
‘T
_-__
1:
l&l,,J \
diacylglyced IP6
i tw+ll
T----,
/ Y
I
79 _-___-_-_-B--B_
C and IPs may play a role in mc diating the inhibition of f,,He and IWM)(Ref. 1). The reduction in evoked glutamate release could involve block of voltage-sensitive Ca2+ channels. This is an effect which haa been observed by some authors’s, although not in the study by Charpak et a!. discussed above. Metabotropic receptor activation may also produce similar effects in other parts of the brain. For example, it has previously been shown that the effects of glutamate applied to the nucleus of the solitary tract are only partially blocked by kynurenate and other ionotropic glutamate receptorantaSonists19. Recent work has demonstratedthat stim~ti~ of the solitary tract produces a Ea2+sensitive, slow depolarization of
:
neurons in the nucleus that is mMb!dbytTil?C+ACPD(S.s.chum et al., unpublished). Fidly, ftlnsACPDalao&p&r&emneumnain thedoreoldanlscpkdnudeusof the rat20, bandreduces glutam& rebe at excitatory synapses in the striat&n Asin&atadatthe f this article, 1 tM duced by Pans-ACPD in the hippocampus w also produced bymwuinicqpnists.lnseved other instences, CM5 effiw of norepinepiuine med&ed by alsdmw+rs have d80 been shown to be dmw. Thus, there appearatokananqiqgroup of ncurotnnanitbr rxq&m that canproduce&wexdtationinthe CNS tbmugh the a8me eharacteristic grou of w events. Thereare J er group0 of recep-
TiPS - October 1991/Vol. 121 tors that are also associated with tropic receptor activation in the particular molecular actions. For CNS. It has been shown that the example, there is the group that EPSP recorded in cerebellar directly activates ion channels Purkinje neurons following acnicotinic, GABA.+ tivation of parallel fibers can be (e.g. SHTJ, glycine), while another group is reduced for a considerable period associated with the G proteinof time by concomitant activation mediated activation of K+ conof the climbing fiber input onto ductances and inhibition of Ca?+ the jdssie ceW. This effect, cakd ‘long-term depression’ (LTD), channels (e.g. GABAs, S-l-IT,, adenosine A,, opiate, a2-adrenoappears to be partly mediated ceptors, etc.). It is comforting to through a metabotropic type of know that the previously enigglutamate recepto-. Digital matic metabotropic receptor actuimaging experiments conducted ally fits so nicely into a known on cerebellar Purkinje cells have pattern of receptor physiology. shown that metabotropic receptor However, further complexity agonists cause Caz+ mobrtization in Purkinje neurons that is parmay be expected for metabotropic ticularly localized to the dendritic receptors. It can be seen that the regions of these cells31a2.As in the effects of tram-ACPD so far identified represent a subgroup of hippocampus, agonists also dethose produced by muscarinic polarize Purldnje cells. However, agonists. We know that there are in this case the mechanism does at least five types of muscarinic not appear to involve inhibition of a K+ current, but may instead receptor. It is quite likely that the different groups of muscarinic involve activation of Na+-Ca2+ effects are the result of activation exchangeu. Further studies supof different receptor subtypes. port a role for metabotropic recepThere are already plenty of inditors in the production of LTD, and cations that there may be several also long-term ptentiation in forms of metabotmpic receptor as the hippocampus Js [see Anwyl, well. For example, the antagonists R. (1991) TiPS, 12,324-3261. AP3 and AP4 blocked glutamateThe various examples discussed and ACPD-induced IPs synthesis’ above clearly suggest that we shall see a large number of reports in and Ca2’ mobilization in some the near future describing a cases=, but not in others=. Interwealth of trans-ACPD effects in estlngly, AP3 bl& none of the many regions of the brain. For the elechophysiologlcal effects of trans-ACPD discus& above1z*16~1s. pharmacologist this is very excitOn the other hand, AP3 does ing news. Thus, even though the pharmacology of NMDA and block hens-ACPD- and glutamatekainate/AMPA receptors has prostimulated IPs production when duced potential therapeutic adbrain mRNA is injected into Xenopus oocyte~“~. However, it vances in a number of key areas, glutamate receptor neuropharmafails to block the effects of quiscology appears to have a lot more qualate in the same eggs”. Furthermore, none of the electromileage in it yet. physiological effects of transRICHARD J. MILLER ACPD discussed above is sensitive to pertussis toxin treatment Departmentof Phanrco/ogicsl ml Physio(where this has been investi/ogicul sciences. Unimrsity of Chicup, 947 gated)‘2,‘8. However, the effects of E. 58th Streer,Chicago. IL 60637. IJSA. metabotropic receptor a onists on lP3 production and Ca 28 mobilizRefmnces ation in neuro&, and oocytes3*” I Nhll, R. A., Maknka, R. C. and Kauer, have sometimes been observed to J. A. (19%)PhwsM. Rev. 70.513465 be blocked by such treatment (or 2 w3ch&pp. D:, Bockaert. J. and Skdeczek, F. (1990) Trrnds Phammol. at least partially blocked). If inSri. 11,506-515 deed multiple forms of G protein3 Masu, M., Tanabe, Y., Tsuchida, K., linked glutamate receptors do Sbi~emoto, R. and Nakanlshi, S. (1991) exist, we should know their identNalnm 349,76&765 ity relatively soon as one member 4 Watkins, ). L, Krogwpard-Larsan. P. md Honor& I’. (1990)TrendsPhwmacot. of the family has already been Sci. 11,25-34 cloned3J5 5 Palmer, E., Monaghan, D. T. and There 6 at least one other relaF;ma&W. (19B9)Eur. 1. Plrarmad. tively well-established electro6 H&g, P. M., Bmdt, 0. S. and Snyder, physiological effect of metabo-
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241(Sl), R12 32 Collingrid~, C. L. and Abbott, A. (1991)TrendsPharmscd. Sci. 12,169-170 33 Kn6pfe1, T. and Staub, C. (199’0 Pfhregers Arch. 24l(Sl), R12 34 Stanton, I? K., Chattarji, S. and Sejnowski, C. (1991)Neumsci’L&t. . 127. 61-66 35 McGuinnass, N., Anwyi, R. and Rowan, hi. (1991)Eur./. Pkamfacol. 197,251~232 36 Cu. Y. and Huang, L-Y. (1991) Neuron 6.777484 37 Miller, R. J. Trends Neumsci. (in pmss) 38 Mar&n, N. V., Zucker, R. 5.. Mush. S. 1. and Adams, P. R. (1991)Neumn 6. 53.i-545
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