title: Agonist-independent GPCR activity regulates anterior-posterior targeting of olfactory sensory neurons.
abstract: G-protein-coupled receptors (GPCRs) are known to possess two different conformations, active and inactive, and they spontaneously alternate between the two in the absence of ligands. Here, we analyzed the agonist-independent GPCR activity for its possible role in receptor-instructed axonal projection. We generated transgenic mice expressing activity mutants of the β2-adrenergic receptor, a well-characterized GPCR with the highest homology to odorant receptors (ORs). We found that mutants with altered agonist-independent activity changed the transcription levels of axon-targeting molecules--e.g., Neuropilin-1 and Plexin-A1--but not of glomerular segregation molecules--e.g., Kirrel2 and Kirrel3--thus causing shifts in glomerular locations along the anterior-posterior (A-P) axis. Knockout and in vitro experiments demonstrated that Gs, but not Golf, is responsible for mediating the agonist-independent GPCR activity. We conclude that the equilibrium of conformational transitions set by each OR is the major determinant of expression levels of A-P-targeting molecules.
authors.affiliation: Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo 113-0032, Japan; Department of Brain Function, School of Medical Science, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Nakashima
authors.forename: Haruki
authors.initials: H
authors.lastname: Takeuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imai
authors.forename: Harumi
authors.initials: H
authors.lastname: Saito
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.forename: Takaya
authors.initials: T
authors.lastname: Abe
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Lee S
authors.initials: LS
authors.lastname: Weinstein
authors.forename: C Ron
authors.initials: CR
authors.lastname: Yu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Storm
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Nishizumi
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sakano
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009833:Olfactory Pathways / Q000166:cytology / Q000196:embryology*; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D018035:Receptors, Odorant / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D018343:Receptors, Adrenergic, beta-2; D018035:Receptors, Odorant
references.citation: Neuron. 2003 Dec 18;40(6):1147-60
references.pmid: 14687549
references.citation: Annu Rev Neurosci. 2011;34:467-99
references.pmid: 21469960
references.citation: Cell. 1991 Apr 5;65(1):175-87
references.pmid: 1840504
references.citation: J Neurochem. 2008 Dec;107(5):1261-70
references.pmid: 18803693
references.citation: Nature. 2007 Nov 22;450(7169):503-8
references.pmid: 17989651
references.citation: Nature. 2011 Jan 13;469(7329):175-80
references.pmid: 21228869
references.citation: Development. 2007 Jul;134(13):2481-9
references.pmid: 17537788
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8715-20
references.pmid: 9671744
references.citation: Nat Rev Endocrinol. 2011 Jun;7(6):362-72
references.pmid: 21301490
references.citation: Neuron. 2000 Sep;27(3):487-97
references.pmid: 11055432
references.citation: Eur J Neurosci. 2003 Nov;18(9):2425-32
references.pmid: 14622143
references.citation: Cell. 2004 Nov 24;119(5):679-91
references.pmid: 15550249
references.citation: Eur J Neurosci. 2011 Jan;33(2):205-13
references.pmid: 21105914
references.citation: Neuron. 2010 Aug 26;67(4):530-42
references.pmid: 20797531
references.citation: J Neurobiol. 2002 Dec;53(4):556-67
references.pmid: 12436420
references.citation: Neuron. 1998 Jan;20(1):69-81
references.pmid: 9459443
references.citation: Cell. 2013 Jan 31;152(3):532-42
references.pmid: 23374348
references.citation: Cold Spring Harb Perspect Biol. 2010 Nov;2(11):a001768
references.pmid: 20880989
references.citation: Cell. 2006 Dec 1;127(5):881-4
references.pmid: 17129775
references.citation: J Neurosci. 1999 Mar 1;19(5):1691-7
references.pmid: 10024355
references.citation: Cell. 1996 Nov 15;87(4):675-86
references.pmid: 8929536
references.citation: J Neurosci. 2005 Apr 6;25(14):3586-92
references.pmid: 15814789
references.citation: J Biol Chem. 1988 Nov 5;263(31):15985-92
references.pmid: 2846532
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 28;101(39):14168-73
references.pmid: 15377787
references.citation: Science. 1998 Mar 27;279(5359):2108-12
references.pmid: 9516112
references.citation: Nat Protoc. 2008;3(9):1402-13
references.pmid: 18772867
references.citation: Trends Pharmacol Sci. 2000 Jan;21(1):24-8
references.pmid: 10637652
references.citation: Biochem J. 1992 Apr 1;283 ( Pt 1):1-19
references.pmid: 1314560
references.citation: Nat Neurosci. 2000 Jul;3(7):687-93
references.pmid: 10862701
references.citation: Nature. 2011 Jul 19;477(7366):549-55
references.pmid: 21772288
references.citation: Science. 2003 Dec 19;302(5653):2088-94
references.pmid: 14593185
references.citation: Neurosci Lett. 1989 Dec 4;106(3):241-8
references.pmid: 2601879
references.citation: Sci Signal. 2009 Mar 03;2(60):ra9
references.pmid: 19261596
references.citation: J Neurophysiol. 2013 Jul;110(1):55-62
references.pmid: 23596334
references.citation: Trends Pharmacol Sci. 2006 Feb;27(2):92-6
references.pmid: 16406086
references.citation: Cell. 1994 Dec 30;79(7):1245-55
references.pmid: 7528109
references.citation: Cell. 1998 Apr 3;93(1):47-60
references.pmid: 9546391
references.citation: Cell. 2006 Dec 1;127(5):1057-69
references.pmid: 17129788
references.citation: Cell. 1994 Dec 16;79(6):981-91
references.pmid: 8001145
references.citation: Cell. 1994 Sep 9;78(5):823-34
references.pmid: 8087849
references.citation: Cell. 2004 Jun 11;117(6):833-46
references.pmid: 15186782
references.citation: J Gen Physiol. 2010 Nov;136(5):529-40
references.pmid: 20974772
references.citation: Curr Opin Neurobiol. 2008 Jun;18(3):251-60
references.pmid: 18721880
references.citation: Science. 2006 Oct 27;314(5799):657-61
references.pmid: 16990513
references.citation: Neuron. 2004 May 27;42(4):553-66
references.pmid: 15157418
references.citation: Cell. 2010 Jun 11;141(6):1056-67
references.pmid: 20550939
references.citation: Nature. 2009 May 21;459(7245):356-63
references.pmid: 19458711
references.citation: Nat Neurosci. 2002 Feb;5(2):124-33
references.pmid: 11802173
references.citation: J Neurochem. 2001 Jul;78(2):325-38
references.pmid: 11461968
references.citation: Science. 2009 Jul 31;325(5940):585-90
references.pmid: 19589963
references.citation: J Biol Chem. 1998 May 1;273(18):5109-16
references.pmid: 9556548
references.citation: Trends Pharmacol Sci. 2007 Aug;28(8):397-406
references.pmid: 17629961
references.citation: Neuron. 2007 Oct 25;56(2):284-300
references.pmid: 17964246
references.citation: Anal Biochem. 1993 Oct;214(1):70-6
references.pmid: 8250257
references.citation: J Biol Chem. 2001 Aug 3;276(31):29171-7
references.pmid: 11375997
references.citation: Proc Natl Acad Sci U S A. 2005 May 17;102(20):7386-91
references.pmid: 15883378
references.citation: Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):1039-44
references.pmid: 17215378