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From the results obtained from in vivo and in vitro disruption of Go/i subgroup of G proteins in Or22a neurons, we proposed a model for insect olfactory signaling (for results see chapter 3), in which the activated Gβγ heterodimer plays a role in signaling.
We think that Gβγ heterodimer can act directly on OR-Orco complex and lead to or enhance the influx of cations. This hypothesis needs to be evaluated. Cells expressing dORs can be stimulated with or without odorants and with or without intracellular injection of Gβγ heterodimer and by this way we can evaluate our hypothesis. In order to test this hypothesis, Xenopus oocytes (stage V and VI) or HEK cells can be used as an experimental model and odor evoked currents can be quantified with or without intracellular injection of the protein or the m-RNA coding for Gβγ heterodimer. I used Xenopus oocytes as an experimental model to test this hypothesis, but the experiments were failed because in my hands dORs were non-functional in these cell systems (dORs were detected by western blot in cytoplasmic fraction but not on the membrane fraction;
data not shown). Hence one can use HEK cells (dORs are functional in these cells) as an experimental model and test this hypothesis in future. Odor evoked currents of HEK293 cells (technique needs to be developed, previously we measured odor evoked calcium changes) expressing dORs together with or without the gene encoding for Gβγ heterodimer can be quantified. Co-expression of Gβγ heterodimer may enhance the odor response and could indicate the role of Gβγ heterodimer in signaling. But if Gβγ heterodimer can mimic odor stimulation cannot be tested easily in HEK cells. May be we can try to stimulate (injection via pressure) the cells with Gβγ heterodimer via intracellularly injected glass pipette. This method needs to be validated and maybe we can find the answer for our question in the end.
From the results obtained from in vivo disruption of Go and Gq subgroup of G proteins in dendro-somatic compartment and in axon terminals of Or92a neurons, we concluded that Go and Gq modulates the odor response in periphery and plays a role in presynaptic excitation and inhibition possibly via the activity of neurotransmitters (for more details see Chapter 4). But the modulation observed in the axon terminals (synaptic output) could be still attributed by the modulation in the periphery, so it is important to measure the electrical activity of Or92a ORNs (single sensillum recordings (SSRs)).
Results of SSRs could indicate how much the modulation observed in the axon terminals is due to the modulation mediated in the periphery. From the results obtained in the dendro-somatic compartment, we proposed a putative model for the modulation mediated by Go and Gq;odor induced transduction in Or92a neurons involves several parallel processes (both ionotropic and metabotropic pathways contribute to) and these processes are modulated by Go and Gq. But “why” such a model is ecologically relevant is not addressed in our experiments. Or92a responds to food odorants (odorants that activate the receptor strongly (best ligand) known to date have buttery and fruity (grape)
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flavor), we speculate that a hungry fly could activate either Go or Gq pathway and modulates the transduction cascade, leading to the high sensitivity of the receptor, whereas a non hungry fly could activate both pathways and hence the sensitivity of the receptor is unchanged. In order to test this hypothesis, one can measure odor induced calcium changes (dendro-somatic compartment) in hungry or satiated flies (all genotypes tested in Chapter 4 should be tested). If any one of the pathways (Go or Gq pathway) is linked to the state of an animal then the odor response of the control flies will differ and that can correlate with the response observed in mutants in previous experiments. Also the response of the mutant flies will be altered if they play a role in modulation of the odor response depending on the state of the animal that we tested and these results could indicate the necessity of modulation of odor response and its ecological relevance.
Moreover the model we proposed for the modulation mediated by Go and Gq is highly putative. Involvement of potassium channels (GIRK or Kir channels) in odor responses needs to be tested. Drosophila genome encodes for three Kir channel proteins;
Ir, IrK2 and IrK3 and all these proteins are expressed in adult head and brain. Mutations targeting to any of these proteins in Or92a neurons could indicate the involvement of these proteins in odor responses. RNAi construct is available for one of the Kir channels (IrK2 or Kir2.1), which allows for physiological experiments on ORNs lacking this channel. If the modulation is carried out by IrK2 channel, then the ORNs lacking this channel should be hyperexcitable like the Go mutant.
From the results obtained in the axon terminals, we proposed a model for the modulation mediated by Go and Gq; Go and Gq plays a role in pre-synaptic inhibition or excitation respectively possibly via the activity of neurotransmitters. We proposed that gamma-aminobutyric acid (GABA; inhibitory neurotransmitter) or acetylcholine (Ach;
excitatory neurotransmitter) could be the neurotransmitter involved. GABA receptors (GABAR) were shown to play a role in pre-synaptic inhibition of Drosophila ORNs (Olsen and Wilson, 2008; Root et al., 2008) and thus it can support our hypothesis (activation of Go by GABABR may lead to pre-synaptic inhibition). Pharmacological experiments targeting these two neurotransmitters (antagonists specific to these receptors; GABABR and m-AchR) can give us an idea about the modulation mediated by Go and Gq. If the modulation observed is via these two neurotransmitters then the odor responses observed with the presence of the pharmacon will be similar as observed in the mutants. All these experiments can give us an insight about why insects uses complex transduction cascade for olfactory signaling.
Above all in our experiments we didn’t show the direct interaction of the OR with the G protein. Interaction of the insect ORs with G proteins are greatly unknown.
Which of the protein (OR or Orco) activates the G protein is unknown; it could be also possible that OR-Orco complex can activate the G protein and not the individual
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protein. In order to elucidate the direct coupling between ORs and G proteins several biochemical experiments can be performed like pull down assays, radioactive labeling experiments and non radioactive labeling experiments (e.g. europium-labeled GTP assay). Also by using these assays we can find which of the protein or the complex activates the G proteins.
133
Summary
Intracellular signaling in insect olfactory receptor neurons remains unclear, with both metabotropic and ionotropic components being discussed. This doctoral thesis investigates the role of heterotrimeric G proteins in olfactory signaling of insects.
Drosophila odorant receptors, Or22a and Or92a were used as the model for insect ORs and the role of G proteins; Go/i subgroup or Go and Gq proteins respectively, in these neurons for olfactory signaling was studied by combined in vivo and in vitro approach. Go/i subgroup of G proteins contributed to the odor responses both for the fast (phasic) and for the slow (tonic) response component and the signaling is mediated by the Gβγ subunits of the heterotrimeric Go/i proteins. In vivo disruption of Go and Gq modulated the odor response of Or92a neurons in the periphery and also played a role in pre-synaptic excitation and inhibition possibly via the activity of neurotransmitters. From these results we could conclude that different ORs activate a G protein to a varying degree and an OR can activate more than one G protein upon odor detection. In general we could conclude that insects use multiple pathways for olfactory signaling, and activates diverse G proteins (metabotropic signaling pathway) upon odor detection.
These results add an intriguing component to the still open full picture of insect olfactory transduction.
134
Zusammenfassung
Die intrazelluläre Signalübertragung in olfaktorischen Rezeptorneuronen bei Insekten ist bis heute unklar. Es werden sowohl metabotrope, als auch ionotrope Komponenten in diesem Kontext diskutiert. In dieser Doktorarbeit wird die Rolle von heterotrimeren G Proteinen bei der olfaktorischen Signalübertragung in Insekten untersucht. Als Modellrezeptoren wurden die Duftrezeptoren Or22a und Or92a von Drosophila verwendet und die Rolle von G Proteinen, speziell der Untergruppen Go/i, Go and Gq, in der olfaktorischen Signalübertragung mit kombinierten in vivo und in vitro Ansätzen untersucht. Wir konnten zeigen, dass die Go/i Untergruppe der G-Proteine sowohl zu der schnellen (phasischen) Kompontene, als auch zu der langsamen (tonischen) Komponente von Duftantworten beiträgt. Die Signalübertragung wird durch die Gβγ Untereinheiten der heterotrimeren Go/i Proteine vermittelt. In vivo Zerstörung von Go und Gq regulierte die Duftantwort von Or92a Neuronen in der Peripherie und spielte ebenfalls eine Rolle bei der präsynaptischen Erregung und Inhibition, möglicherweise durch die Aktivität von Neurotransmittern. Anhand dieser Ergebnisse konnten wir schliessen, dass verschiedene ORs ein G Protein unterschiedlich stark aktivieren und dass ein OR mehr als ein G Protein bei Duftdetektion aktivieren kann. Im Allgemeinen konnten wir schliessen, dass Insekten mehrere Wege zur olfaktorischen Signalübertragung nutzen und dass diverse G Proteine (metabotrope Signalübertragung) bei der Duftdetektion aktiviert werden. Diese Ergebisse fügen dem immer noch offnen Gesamtbild der olfaktorischen Transduktion bei Insekten eine faszinierende Komponente hinzu.
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