De-Orphanizing Olfaction

Hiroaki Matsunami

Duke University

Cliff and C. diff - Smelling the diagnosis

BMJ

Bomers et al., 12

How can he do it?

A broad-, sensitive and fine-tuned chemical

detector

Nasal Mucus

OlfactorySensory Neurons

Olfactory Bulb

Olfactory Cilia

The mammalian olfactory system

The Nobel

Foundation

One olfactory neuron – one receptor rule

OR genes

The olfactory signaling pathway

6

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

µM

µM

µM

mM

nM

Saito, Mainland 09

Large-scale

in vitro

screening

with

human

and

mouse

ORs

OR functional variation affects odor perception in humans

Individual OR genes and odor perception

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