De-Orphanizing Olfaction Hiroaki Matsunami Duke University
Transcript of De-Orphanizing Olfaction Hiroaki Matsunami Duke University
Nasal Mucus
OlfactorySensory Neurons
Olfactory Bulb
Olfactory Cilia
The mammalian olfactory system
The Nobel
Foundation
The olfactory signaling pathway
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monophosphate (cAMP). Finally, this increase in cAMP opens cyclic nucleotide
gated cation (CNG) channels, causing depolarization of the neuron (Fig. 1-3)
(Firestein, 2001; Mombaerts, 1999, 2004a).
Figure 1-3: Olfactory signal cascade. When an odor molecule binds to an OR, the GTP
bound form Gaolf subunit stimulates adenylyl cyclase III (ACIII) to convert ATP into cAMP.
This increase in cAMP opens cyclic nucleotide-gated (CNG) cation channels, causing
depolarization of the OSN and transmission of the signal to the olfactory bulb.
1.3 Odorant receptors and their ligands
The combinatorial code
If, on average, there are 1000 ORs encoded in the mammalian genome
and 10,000-100,000 chemically diverse odors in the environment, how is it that
the olfactory system can detect and discriminate these odors? The answer is the
olfactory system functions using a combinatorial strategy. This means that a
single type of odor molecule is recognized by multiple ORs and a single OR can
be activated by multiple odors (Fig. 1-4) (Firestein, 2001; B Malnic, et al., 1999;
Mombaerts, 2004a).
Golf
Number of ORs
Human 396
Mouse 1130
Rat 1207
Dog 811
The human G-protein coupled receptors and the ORs
A combinatorial odor coding
(Malnic et al. 1999)
1. How many and which ORs are activated by a given odor?
2. How does each OR contribute odor perception?
Functional expression of ORs in heterologuos cells:
Importance of Receptor-Transporting Proteins (RTPs)
Saito et al., 04, Zhuang et al., 06
Cell Surface Expression
EC50
Each individual has a unique set of
functional OR repertoire
functionally same as reference
functionally different
Acknowledgements:Current and Former lab members
Yue JiangNatalie GongNeha SharmaTing ZhouJianghai HoMingshan ChienJessica NiElise BrugueraSafa Kaleem
Joel MainlandKaylin AdipietroSandeepa DeyHanyi ZhuangRose Li Peter DongLinda LiuMimi ZhanZoya QureshyRich RobertsAkemi ToyamaYoshi IshimaruMomo KubotaQiuyi ChiFelix HsuHarumi SaitoAubrey Bonhivert
Reagents, Equipments,
Gilad BarneaRichard AxelDoug MarchukHubi AmreinJorn CoersMarc CaronJoe HeitmanRaphael ValdiviaDebby Silver
Funding: NIH-NIDCD, HFSP, DARPA, Chancellor's Discovery Program
Collaborators
Leslie Vosshall
Andreas Keller
Kathrine Lunde
Bjørg Egelandsdal
Julia Walker
Eric Block
Minghong Ma
Ian Davison
Mike Ehlers
IGSP Genome sequencing coreDCI DNA analysis facilityDCI Flow cytometry facilityDuke Neurotransgenic laboratory