Orthosteric- and allosteric-induced ligand-directed trafficking at GPCRs.
Many orthosteric agonists differentially activate downstream effectors of GPCRs. Such defined induction of signaling has strongly supported the hypothesis termed 'ligand-directed trafficking of receptor signaling' (LDTRS). More recently, subtype-selective GPCR activators, such as allosteric agonists and positive allosteric modulators, have also exhibited the capacity to activate specific signaling pathways. Based on this finding, it may be possible to achieve ligand-specific receptor active states that optimize the biological responses specific to GPCRs. This review discusses recent studies in which both orthosteric and allosteric compounds have been demonstrated to induce LDTRS.
Digby
Gregory J
GJ
Vanderbilt University School of Medicine, Department of Pharmacology, 12415D MRBIV (Langford), Nashville, TN 37232, USA.
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
D000494:Allosteric Regulation; D000495:Allosteric Site; D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry; D011485:Protein Binding; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*; D013237:Stereoisomerism
D008024:Ligands; D004364:Pharmaceutical Preparations; D043562:Receptors, G-Protein-Coupled
J Biol Chem. 1996 Aug 9;271(32):19021-4
8702570
Br J Clin Pharmacol. 2004 Apr;57(4):373-87
15025734
Biol Reprod. 1998 Sep;59(3):579-86
9716556
J Neurochem. 2000 Mar;74(3):1068-78
10693938
Mol Pharmacol. 2005 Aug;68(2):393-402
15870392
Endocr Rev. 2003 Dec;24(6):765-81
14671004
Nat Rev Drug Discov. 2009 Jan;8(1):41-54
19116626
Annu Rev Physiol. 2007;69:483-510
17305471
Mol Pharmacol. 1994 May;45(5):890-8
8190105
Biochemistry. 1999 Feb 23;38(8):2272-8
10029519
J Neurochem. 2001 Jan;76(2):509-19
11208914
J Pharmacol Exp Ther. 2005 Dec;315(3):1212-9
16135701
Annu Rev Pharmacol Toxicol. 2002;42:349-79
11807176
FEBS Lett. 2001 Mar 30;493(2-3):101-5
11287004
Annu Rev Pharmacol Toxicol. 1996;36:429-59
8725397
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9914-9
9707575
Trends Pharmacol Sci. 1997 Oct;18(10):355-62
9357320
Mol Pharmacol. 2009 Mar;75(3):577-88
19047481
Mol Pharmacol. 2007 Feb;71(2):549-57
17090705
Mol Pharmacol. 1998 Jul;54(1):94-104
9658194
J Theor Biol. 1967 Aug;16(2):306-20
6048545
Br J Pharmacol Chemother. 1956 Dec;11(4):379-93
13383117
Biochem J. 1996 May 1;315 ( Pt 3):883-8
8645172
Mol Pharmacol. 1973 Jan;9(1):1-9
4685448
Mol Pharmacol. 1998 Apr;53(4):759-65
9547368
Neuropsychopharmacology. 2010 Mar;35(4):855-69
19940843
Ann N Y Acad Sci. 1998 Dec 15;861:97-103
9928245
Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):116-20
8552586
Science. 2005 Apr 22;308(5721):512-7
15845844
Trends Pharmacol Sci. 2009 Mar;30(3):148-55
19201489
Trends Pharmacol Sci. 2007 Aug;28(8):416-22
17644195
J Biol Chem. 2010 Mar 5;285(10):7459-74
20051519
Cell Signal. 1991;3(6):547-57
1786205
J Biol Chem. 2006 Aug 4;281(31):21837-21847
16754664
J Pharmacol Exp Ther. 2009 Dec;331(3):1086-95
19767446
Neuron. 1998 Nov;21(5):959-80
9856454
Trends Pharmacol Sci. 1995 Jul;16(7):232-8
7667897
J Pharmacol Exp Ther. 2007 Jan;320(1):1-13
16803859
J Biol Chem. 2006 Apr 21;281(16):10856-64
16492667
J Biol Chem. 1990 Jun 25;265(18):10320-6
2162345
Mol Pharmacol. 2002 Apr;61(4):768-77
11901215
Pharmacol Ther. 2003 Jul;99(1):25-44
12804697
J Biol Chem. 2008 Oct 24;283(43):29312-21
18723515
J Biol Chem. 2001 Jan 26;276(4):2474-9
11036069
Ann N Y Acad Sci. 1993 Sep 24;695:300-3
8239299
Nat Rev Drug Discov. 2002 Sep;1(9):727-30
12209152
Mol Endocrinol. 1996 Dec;10(12):1697-707
8961278
Trends Pharmacol Sci. 1994 Nov;15(11):408-9
7855903
J Pharmacol Exp Ther. 2007 Jun;321(3):1193-207
17392404
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2449-54
11226259
Trends Pharmacol Sci. 2007 Aug;28(8):423-30
17659355
Curr Opin Pharmacol. 2003 Oct;3(5):551-6
14559102
J Pharmacol Exp Ther. 2008 Nov;327(2):365-74
18664591
BMC Pharmacol. 2009 Dec 02;9:14
19951444
Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16657-62
17925438
ACS Chem Neurosci. 2010 Aug 18;1(8):542-551
20835371
Br J Pharmacol. 2001 Feb;132(4):950-8
11181437
Pharmacol Rev. 2002 Jun;54(2):323-74
12037145
Mol Pharmacol. 1997 Jul;52(1):144-54
9224824