0 5 FK506 FK506 NNP 6 9 and and CC 10 21 ciclosporin ciclosporin NN 21 22 : : : 23 32 molecular molecular JJ 33 39 probes probe NNS 40 43 for for IN 44 52 studying study VBG 53 66 intracellular intracellular JJ 67 73 signal signal NN 74 86 transduction transduction NN 86 87 . . . 89 92 The the DT 93 111 immunosuppressants immunosuppressant NNS 112 123 ciclosporin ciclosporin NN 124 127 and and CC 128 133 FK506 FK506 NNP 134 139 block block VBP 140 143 the the DT 144 160 Ca(2+)-dependent ca(2+)-dependent JJ 161 180 signal-transduction signal-transduction NN 181 188 pathway pathway NN 189 198 emanating emanate VBG 199 203 from from IN 204 207 the the DT 208 214 T-cell t-cell NN 215 223 receptor receptor NN 223 224 , , , 225 232 thereby thereby RB 233 243 inhibiting inhibit VBG 244 247 the the DT 248 258 activation activation NN 259 261 of of IN 262 268 helper helper NN 269 270 T t NN 271 276 cells cell NNS 276 277 . . . 278 283 Using use VBG 284 289 these these DT 290 295 drugs drug NNS 296 298 as as IN 299 305 probes probe NNS 305 306 , , , 307 315 chemists chemist NNS 316 319 and and CC 320 330 biologists biologist NNS 331 335 have have VBP 336 345 uncovered uncover VBN 346 353 several several JJ 354 367 intracellular intracellular JJ 368 378 signalling signalling NN 379 388 molecules molecule NNS 389 397 bridging bridge VBG 398 401 the the DT 402 412 generation generation NN 413 415 of of IN 416 432 second-messenger second-messenger NN 433 437 Ca2+ ca2+ NN 438 442 ions ion NNS 443 446 and and CC 447 450 the the DT 451 466 transcriptional transcriptional JJ 467 477 activation activation NN 478 480 of of IN 481 485 IL-2 il-2 NN 485 486 , , , 487 492 among among IN 493 498 which which WDT 499 502 are be VBP 503 513 calmodulin calmodulin NN 513 514 , , , 515 526 calcineurin calcineurin NN 527 530 and and CC 531 534 the the DT 535 542 nuclear nuclear JJ 543 549 factor factor NN 550 552 of of IN 553 562 activated activate VBN 563 564 T t NN 565 570 cells cell NNS 571 572 ( ( ( 572 577 NF-AT NF-AT NNP 577 578 ) ) ) 578 579 . . . 580 585 Hence hence RB 585 586 , , , 587 591 Ca2+ ca2+ NN 592 597 binds bind VBZ 598 600 to to TO 601 611 calmodulin calmodulin NN 611 612 , , , 613 620 leading lead VBG 621 623 to to TO 624 627 the the DT 628 635 binding binding NN 636 638 of of IN 639 649 calmodulin calmodulin NN 650 652 to to TO 653 664 calcineurin calcineurin NN 664 665 ; ; : 666 669 the the DT 670 679 activated activate VBN 680 691 calcineurin calcineurin NN 691 692 , , , 693 695 in in IN 696 700 turn turn NN 700 701 , , , 702 705 may may MD 706 721 dephosphorylate dephosphorylate VB 722 725 the the DT 726 737 cytoplasmic cytoplasmic JJ 738 745 subunit subunit NN 746 748 of of IN 749 754 NF-AT NF-AT NNP 754 755 , , , 756 765 resulting result VBG 766 768 in in IN 769 772 its its PRP$ 773 786 translocation translocation NN 787 791 from from IN 792 795 the the DT 796 805 cytoplasm cytoplasm NN 806 810 into into IN 811 814 the the DT 815 822 nucleus nucleus NN 823 825 to to TO 826 830 form form VB 831 832 a a DT 833 842 competent competent JJ 843 858 transcriptional transcriptional JJ 859 868 activator activator NN 868 869 . . . 870 872 As as IN 873 882 described describe VBN 883 885 by by IN 886 889 Jun Jun NNP 890 893 Liu Liu NNP 893 894 , , , 895 900 these these DT 901 906 drugs drug NNS 907 915 manifest manifest VBP 916 921 their their PRP$ 922 929 effects effect NNS 930 932 in in IN 933 935 an an DT 936 949 unprecedented unprecedented JJ 950 957 fashion fashion NN 957 958 . . . 959 963 They they PRP 964 966 do do VBP 967 970 not not RB 971 979 directly directly RB 980 989 intercept intercept VB 990 1003 intracellular intracellular JJ 1004 1014 signalling signalling NN 1015 1024 molecules molecule NNS 1024 1025 . . . 1026 1033 Instead instead RB 1033 1034 , , , 1035 1039 they they PRP 1040 1044 form form VBP 1045 1050 tight tight JJ 1051 1060 complexes complex NNS 1061 1065 with with IN 1066 1069 two two CD 1070 1079 different different JJ 1080 1087 classes class NNS 1088 1090 of of IN 1091 1099 abundant abundant JJ 1100 1109 cytosolic cytosolic JJ 1110 1119 receptors receptor NNS 1120 1126 called call VBD 1127 1140 immunophilins immunophilin NNS 1141 1145 upon upon IN 1146 1154 entering enter VBG 1155 1158 the the DT 1159 1163 cell cell NN 1163 1164 , , , 1165 1168 and and CC 1169 1181 consequently consequently RB 1182 1189 inhibit inhibit VBP 1190 1195 their their PRP$ 1196 1204 peptidyl peptidyl JJ 1205 1211 prolyl prolyl JJ 1212 1221 cis-trans cis-trans JJ 1222 1231 isomerase isomerase NN 1232 1242 activities activity NNS 1242 1243 . . . 1244 1247 The the DT 1248 1251 two two CD 1252 1264 structurally structurally RB 1265 1273 distinct distinct JJ 1274 1291 immunophilin-drug immunophilin-drug JJ 1292 1301 complexes complex NNS 1302 1306 bind bind VBP 1307 1309 to to TO 1309 1310 , , , 1311 1314 and and CC 1315 1322 inhibit inhibit VBP 1322 1323 , , , 1324 1327 the the DT 1328 1339 phosphatase phosphatase NN 1340 1348 activity activity NN 1349 1351 of of IN 1352 1363 calcineurin calcineurin NN 1363 1364 . . .