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TiPS - August 2992[vol. 121
292 References I Supattapone,S., Worley, p. F., Banban. J. M. and Snyder, ‘3. H. (1988) 1. B&l. &ix. 263, 1530-1534 2 Furuichi, T. et d. (1%9) Nnhtrr 342.3”-38 3 Satoh, T. ct nl. (1990) 1. Cell Bi@!.111. 615-624 4 Meld&i, I. and Pouan, T. (1987) EXP. CPII Rrs. iii, 271-283 5 Tschamer, V., van Prud’hoto. 8.. 6a@ini, M. ad Reuter, H. (1986) Natrrn 324,369-37l 6 Kuno, M. and Gardner, P. (1987) Nature 326.301-304 7 Irvine, R. F. (1990) FEES LCK 263.5-9 8 puhq, J. w. (1986) Cell Calcium7.1-12 9 TS~PTI, R. Y. (1989) Annu. Rev. Ntumi. 12,227-W 10 Sage, S. 0.. Merritt. J. E., Hallam, T. I. and Rink, T. I. (1989) Biochem.I. 258, 923-926 11 Fasolato,C., Pandiella, A., Meldolesi. J. and Pouan, T. (1988) /. Viol. Ckem.263. 17350-17359 12 Penner, R., Matthews, G. and Neher, E. (1986) Nutire 334,499-504 i3 Changya. I., Galiacher. D. v., irvine, R. F. and Petemen, 0. H. (1969; FiZj lett. 251, 43-40 14 Komori, S. and Bolton, T. B. (1990) 1. Physial.Il.&on) 427.395-419 15 Flltney, J. w. (1990) CeII Calcium 11, 611-624 16 Takemun. H., Hughes, A. R., Thashup, 0. and Puhwy, J. W., Jr (1989) J. Biol.
Chcm. 264, I226642271 17 Jackson,T. R., Patterson,5. I., Thasttup, 0. and Hanky, M. R. (1988) Biochcm.J. 2.53,81-B6 18 pmdd, S. J. and schoeffieid-Payne,M. S. (1990) 1. &al. Chrm. 265.12646-12853 19 Gmbovaz, F. et al. 1. CPIIBiol. (in press) 20 Ito, S. et nl. (1991) J. Nrurochrm. 56, 531-540 21 Huan& C. L., Takenawa, T. and Ives, H. E. (1991) 1. Bid. Chcm.266,40&4046 22 Sternweis, I? C. and Pang, I-H. (1990) TrendsPharmrrrol.Sci. 11,X22-126 23 Namsimban, V., Holowka, D., Fewhpll, C. and Baird, B. (1986) 1. Biol.Chum.263, 1%26-1%32 24 SJolander, A., Cmnroos, E., Hammarstrom, 5. and Andemeon, 7. (1990) 1. Biol.Chem 265.20976-20981 25 5age. S. 0.. Reast, R. and Rink, 7: J. (1990) Biorhcm.1.265,675-680 26 Taylor, C. W. (1990) Trends Phmrco/. Sri. 11.269-271 27 Poenie, M., Tsien, R. Y. and SchmittVerbulst. A. M. (1987) EMBO \. 6, 22a-2232 28 uiudennan, K A., Mwwky, M. hf. and PNsS, R. M. (1990) CellRegul, L6B3-691 29 Brooks. R. C.. McCarthy, K. D., Lapetina, E. G. and Morell, P. (1989) 1. Biol. Chtm. 264,2014?-2Ol53 30 Magni, M., Meidohsi, J. and Pandiella, h (1991) /. Bid. Chem.266, 6329-6335 31 Merritt, J. E. et PI. (1990) Br. /. Phmrmacol. 98,6749-67!34 32 Ciatdo, A. and Mekloksi, J. (1990) Eur. 1. Phunnacol.188.417-421 33 Fabotao. C.. pizza, P. and Pozzan, T. (1990) 1. Biol. Chcm. 26S,2ml-20355
SUap95#9:
I-($(3-(4.mettmxy-
pbmyS&opoxyl-4-methoxyphenethyl)IH-imiduok HCI sQsr#). I-{f@bis@-metbwphenyljpqoxyJ)-lH-imidazole HCI
Agonistcontrolcf G proteinlevels morecomplexand subtle
bguMion of G protein levels even more complex and subtle ln a recent article, Mill&an and than Milligan and Green suggest. Green (Tips, June 1991)‘, proposed several mechanisms whereMARY KEEN AND ANKE KRANB by agonists may modulate the reDeperhnent of Phnrmec&gy, Tkc Medical sponsiveness of cells by Controlling School, Unkwsily of Binninghum,Eirmingthe levels of various G proteins. hem B15 2m UK. Miliigan and Green reported studies where the level of G,a (the References (Y subunit of G,) in NGlOB-15 1 Mi&an, G. and Green, A. (1991) Trends Phannacof.Sci. 12.207-299 (neuroblastoma x glioma) cells is 2 Mochly-Rosen, D. et al. (1988) Nahor 333. reduced following exposure to ethanol’, leading to the suggestion 3 EM., Kelly, R., Nobbs, P. and that this effect may be mediated =I (1989) Biochem.Phmnacol. via an increase in extracellular 4K&8,Keen,M.lrNobbs,P.and adenosine levels. However, it MacDenoot, J. (1990) BY.1. phetntacoi.99, seems extremely unlikely that this 309-316 effect of ethanol can explain the J. 5 Keen, M., Kelly, E. and t&&mot, loss of G,a, as pretreatment of Eur. 1. PhormocoL(ii press) 6 Lei& P. J., Cramp, W. A. and NGlO&15 cells with the adenosine Ma&ermot, J. (1asC) 1. B&t. Chem. 239, receptor agonists NECA (5’~Nlxil-I2436 ethykcarboxamido-adenosine) or 7 Hanasaki, K. snd A&a, H. (1989) BioMA (K-L-phen lisopropyladenchim. Bivphys. AC&lOl3,20-35 osine) has no ef rect mi the functioning of G, (Ref. 3). Miiligan and Gmen rightly Pointed out that G protein downregulation is not observed in all tissues. Prostacyclin receptor agonists produce downregulation of G, in NGlOB-15cells, but not in the closely related hybrid cell line Jhinktoa08rine NCB20 (a ‘half-brother’ to NG108Etbanol-smsitivity of GABA1!J4. Miliigan and Green put forinduced Cl’ flux hsbeen rttrlbuted to ward the hypothesis that this type asingleaminoacldIntheyZsubunitof of phenomenon is related to the the multIsubunit, 1igand-gated ion number of receptors and G prochannel, the GA~AAma+or. teins in the cell’. However, it is Ineqerimentswheremouaebrain clear that NGlO&15 and NC%!0 mRNAwas hybridized with a&sense oligonucIeotidea cells express very similar densities of prostacyclin (1P) receptors~, and-&ena&aaaedin&xytes,etbanol suggesting that this may well be enhancement of GABA a&icm was an oversimplification. ModcedbyantisansetoyU,butnotby However, the author’s estimate antisense to other known GABA,, of IP receptor density in NGIOB-15 receptor subnnits, IncIudIng y2s cells is some tenfold higher than (Wafioni,K.A.ctal.,ffeamrt,in~ress). other reported values’,‘! It is possy2Lisoneofthetwoknovmvariantsof ible that these high values do not the y2 subunit that are derived by alternatIve splklng. It is eight amino reflect IP receptor binding at all, acids lonpr than its y2S counterpart. but represent binding of the (unNew deIetIon and Point mutation specified) ligand to the high castudies, qortecl by Keith Wafford pacity, nonspecific prostanoidatthe7thSardin&nCanfereuceon binding sit&s,‘. NeurosclenceinJuue,have&nvnthat Thus, while we wholeheartedly only the sin& se&e residue in tbls agree that regulation of G proteins stretch,a putatives&eforpboaphorylis important in modulating cell ation, is an absolute requiremmt for responsiveness, we would suggest ethanol sensitlvig of the GABA* rethat the mechanisms involved are ceptorcomplex. A.A.
292 References I Supattapone,S., Worley, p. F., Banban. J. M. and Snyder, ‘3. H. (1988) 1. B&l. &ix. 263, 1530-1534 2 Furuichi, T. et d. (1%9) Nnhtrr 342.3”-38 3 Satoh, T. ct nl. (1990) 1. Cell Bi@!.111. 615-624 4 Meld&i, I. and Pouan, T. (1987) EXP. CPII Rrs. iii, 271-283 5 Tschamer, V., van Prud’hoto. 8.. 6a@ini, M. ad Reuter, H. (1986) Natrrn 324,369-37l 6 Kuno, M. and Gardner, P. (1987) Nature 326.301-304 7 Irvine, R. F. (1990) FEES LCK 263.5-9 8 puhq, J. w. (1986) Cell Calcium7.1-12 9 TS~PTI, R. Y. (1989) Annu. Rev. Ntumi. 12,227-W 10 Sage, S. 0.. Merritt. J. E., Hallam, T. I. and Rink, T. I. (1989) Biochem.I. 258, 923-926 11 Fasolato,C., Pandiella, A., Meldolesi. J. and Pouan, T. (1988) /. Viol. Ckem.263. 17350-17359 12 Penner, R., Matthews, G. and Neher, E. (1986) Nutire 334,499-504 i3 Changya. I., Galiacher. D. v., irvine, R. F. and Petemen, 0. H. (1969; FiZj lett. 251, 43-40 14 Komori, S. and Bolton, T. B. (1990) 1. Physial.Il.&on) 427.395-419 15 Flltney, J. w. (1990) CeII Calcium 11, 611-624 16 Takemun. H., Hughes, A. R., Thashup, 0. and Puhwy, J. W., Jr (1989) J. Biol.
Chcm. 264, I226642271 17 Jackson,T. R., Patterson,5. I., Thasttup, 0. and Hanky, M. R. (1988) Biochcm.J. 2.53,81-B6 18 pmdd, S. J. and schoeffieid-Payne,M. S. (1990) 1. &al. Chrm. 265.12646-12853 19 Gmbovaz, F. et al. 1. CPIIBiol. (in press) 20 Ito, S. et nl. (1991) J. Nrurochrm. 56, 531-540 21 Huan& C. L., Takenawa, T. and Ives, H. E. (1991) 1. Bid. Chcm.266,40&4046 22 Sternweis, I? C. and Pang, I-H. (1990) TrendsPharmrrrol.Sci. 11,X22-126 23 Namsimban, V., Holowka, D., Fewhpll, C. and Baird, B. (1986) 1. Biol.Chum.263, 1%26-1%32 24 SJolander, A., Cmnroos, E., Hammarstrom, 5. and Andemeon, 7. (1990) 1. Biol.Chem 265.20976-20981 25 5age. S. 0.. Reast, R. and Rink, 7: J. (1990) Biorhcm.1.265,675-680 26 Taylor, C. W. (1990) Trends Phmrco/. Sri. 11.269-271 27 Poenie, M., Tsien, R. Y. and SchmittVerbulst. A. M. (1987) EMBO \. 6, 22a-2232 28 uiudennan, K A., Mwwky, M. hf. and PNsS, R. M. (1990) CellRegul, L6B3-691 29 Brooks. R. C.. McCarthy, K. D., Lapetina, E. G. and Morell, P. (1989) 1. Biol. Chtm. 264,2014?-2Ol53 30 Magni, M., Meidohsi, J. and Pandiella, h (1991) /. Bid. Chem.266, 6329-6335 31 Merritt, J. E. et PI. (1990) Br. /. Phmrmacol. 98,6749-67!34 32 Ciatdo, A. and Mekloksi, J. (1990) Eur. 1. Phunnacol.188.417-421 33 Fabotao. C.. pizza, P. and Pozzan, T. (1990) 1. Biol. Chcm. 26S,2ml-20355
SUap95#9:
I-($(3-(4.mettmxy-
pbmyS&opoxyl-4-methoxyphenethyl)IH-imiduok HCI sQsr#). I-{f@bis@-metbwphenyljpqoxyJ)-lH-imidazole HCI
Agonistcontrolcf G proteinlevels morecomplexand subtle
bguMion of G protein levels even more complex and subtle ln a recent article, Mill&an and than Milligan and Green suggest. Green (Tips, June 1991)‘, proposed several mechanisms whereMARY KEEN AND ANKE KRANB by agonists may modulate the reDeperhnent of Phnrmec&gy, Tkc Medical sponsiveness of cells by Controlling School, Unkwsily of Binninghum,Eirmingthe levels of various G proteins. hem B15 2m UK. Miliigan and Green reported studies where the level of G,a (the References (Y subunit of G,) in NGlOB-15 1 Mi&an, G. and Green, A. (1991) Trends Phannacof.Sci. 12.207-299 (neuroblastoma x glioma) cells is 2 Mochly-Rosen, D. et al. (1988) Nahor 333. reduced following exposure to ethanol’, leading to the suggestion 3 EM., Kelly, R., Nobbs, P. and that this effect may be mediated =I (1989) Biochem.Phmnacol. via an increase in extracellular 4K&8,Keen,M.lrNobbs,P.and adenosine levels. However, it MacDenoot, J. (1990) BY.1. phetntacoi.99, seems extremely unlikely that this 309-316 effect of ethanol can explain the J. 5 Keen, M., Kelly, E. and t&&mot, loss of G,a, as pretreatment of Eur. 1. PhormocoL(ii press) 6 Lei& P. J., Cramp, W. A. and NGlO&15 cells with the adenosine Ma&ermot, J. (1asC) 1. B&t. Chem. 239, receptor agonists NECA (5’~Nlxil-I2436 ethykcarboxamido-adenosine) or 7 Hanasaki, K. snd A&a, H. (1989) BioMA (K-L-phen lisopropyladenchim. Bivphys. AC&lOl3,20-35 osine) has no ef rect mi the functioning of G, (Ref. 3). Miiligan and Gmen rightly Pointed out that G protein downregulation is not observed in all tissues. Prostacyclin receptor agonists produce downregulation of G, in NGlOB-15cells, but not in the closely related hybrid cell line Jhinktoa08rine NCB20 (a ‘half-brother’ to NG108Etbanol-smsitivity of GABA1!J4. Miliigan and Green put forinduced Cl’ flux hsbeen rttrlbuted to ward the hypothesis that this type asingleaminoacldIntheyZsubunitof of phenomenon is related to the the multIsubunit, 1igand-gated ion number of receptors and G prochannel, the GA~AAma+or. teins in the cell’. However, it is Ineqerimentswheremouaebrain clear that NGlO&15 and NC%!0 mRNAwas hybridized with a&sense oligonucIeotidea cells express very similar densities of prostacyclin (1P) receptors~, and-&ena&aaaedin&xytes,etbanol suggesting that this may well be enhancement of GABA a&icm was an oversimplification. ModcedbyantisansetoyU,butnotby However, the author’s estimate antisense to other known GABA,, of IP receptor density in NGIOB-15 receptor subnnits, IncIudIng y2s cells is some tenfold higher than (Wafioni,K.A.ctal.,ffeamrt,in~ress). other reported values’,‘! It is possy2Lisoneofthetwoknovmvariantsof ible that these high values do not the y2 subunit that are derived by alternatIve splklng. It is eight amino reflect IP receptor binding at all, acids lonpr than its y2S counterpart. but represent binding of the (unNew deIetIon and Point mutation specified) ligand to the high castudies, qortecl by Keith Wafford pacity, nonspecific prostanoidatthe7thSardin&nCanfereuceon binding sit&s,‘. NeurosclenceinJuue,have&nvnthat Thus, while we wholeheartedly only the sin& se&e residue in tbls agree that regulation of G proteins stretch,a putatives&eforpboaphorylis important in modulating cell ation, is an absolute requiremmt for responsiveness, we would suggest ethanol sensitlvig of the GABA* rethat the mechanisms involved are ceptorcomplex. A.A.