The Na+/Ca2+ exchanger NCKX4 governs termination and adaptation of the mammalian olfactory response

Stephan, Aaron B.; Tobochnik, Steven; Dibattista, Michele; Gigante, Crystal M.; Reisert, Johannes; Zhao, Haiqing

doi:10.1038/nn.2943

Cited by 108 publications

(127 citation statements)

References 50 publications

(74 reference statements)

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“…The main contributor to response termination in WT ORNs is the rate of Ca 2ϩ extrusion from olfactory cilia determined mainly by NCKX4 (Stephan et al, 2012). The results presented in this paper and those previously published (Reisert et al, 2007;Kwon et al, 2009) showed a slower response termination in the OMP KO ORNs.…”

Section: Omp's Contribution To the Dynamic Range Of Odorant Sensitivisupporting

confidence: 71%

“…The ciliary cAMP increase opens the olfactory cyclic nucleotide-gated (CNG) channel (Nakamura and Gold, 1987;Firestein et al, 1991) and influx of Na ϩ and Ca 2ϩ (Dzeja et al, 1999) causes ORN depolarization. Ca 2ϩ triggers the activation of the second olfactory transduction channel, an excitatory Ca 2ϩ -activated Cl Ϫ channel TMEM16B/ANO2 (Kleene, 1993;Lowe and Gold, 1993;Stephan et al, 2009;Hengl et al, 2010;Rasche et al, 2010;Sagheddu et al, 2010;Billig et al, 2011). Transduction leads to the generation of APs to convey odor information to the olfactory bulb (OB).…”

Section: Introductionmentioning

confidence: 99%

“…For the odorant response to terminate, cAMP and Ca 2ϩ must return to basal levels for CNG and Cl Ϫ channels to close. Ciliary Ca 2ϩ reduction is achieved by a Na ϩ /Ca 2ϩ extrusion (NCKX4; Stephan et al, 2012). Interestingly, the rate of cAMP degradation is not controlled by the olfactory phosphodiesterases (PDEs) 1C and 4A as neither PDE contributes significantly to response termination (Boccaccio et al, 2006;Cygnar and Zhao, 2009).…”

Section: Introductionmentioning

confidence: 99%

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The Odorant Receptor-Dependent Role of Olfactory Marker Protein in Olfactory Receptor Neurons

Dibattista

Reisert

2016

J. Neurosci.

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Olfactory receptor neurons (ORNs) in the nasal cavity detect and transduce odorants into action potentials to be conveyed to the olfactory bulb. Odorants are delivered to ORNs via the inhaled air at breathing frequencies that can vary from 2 to 10 Hz in the mouse. Thus olfactory transduction should occur at sufficient speed such that it can accommodate repetitive and frequent stimulation. Activation of odorant receptors (ORs) leads to adenylyl cyclase III activation, cAMP increase, and opening of cyclic nucleotide-gated channels. This makes the kinetic regulation of cAMP one of the important determinants for the response time course. We addressed the dynamic regulation of cAMP during the odorant response and examined how basal levels of cAMP are controlled. The latter is particularly relevant as basal cAMP depends on the basal activity of the expressed OR and thus varies across ORNs. We found that olfactory marker protein (OMP), a protein expressed in mature ORNs, controls both basal and odorant-induced cAMP levels in an OR-dependent manner. Lack of OMP increases basal cAMP, thus abolishing differences in basal cAMP levels between ORNs expressing different ORs. Moreover, OMP speeds up signal transduction for ORNs to better synchronize their output with high-frequency stimulation and to perceive brief stimuli. Last, OMP also steepens the dose-response relation to improve concentration coding although at the cost of losing responses to weak stimuli. We conclude that OMP plays a key regulatory role in ORN physiology by controlling multiple facets of the odorant response.

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Section: Omp's Contribution To the Dynamic Range Of Odorant Sensitivisupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Odorant Receptor-Dependent Role of Olfactory Marker Protein in Olfactory Receptor Neurons

Dibattista

Reisert

2016

J. Neurosci.

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“…We and others have used the OMP promoter to force the expression of OR genes (19)(20)(21)(22)(23)(24) as well as to knock out genes via Cre-recombinase (25)(26)(27). However, our current results show that OMP is expressed, at the earliest, 48 h after OR expression is initiated and after axons have reached the OB and drawn proximal to the point of glomerular convergence.…”

Section: Discussioncontrasting

confidence: 60%

Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons

Rodriguez‐Gil

Bartel

Jaspers

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Odorant receptors (OR) are strongly implicated in coalescence of olfactory sensory neuron (OSN) axons and the formation of olfactory bulb (OB) glomeruli. However, when ORs are first expressed relative to basal cell division and OSN axon extension is unknown. We developed an in vivo fate-mapping strategy that enabled us to follow OSN maturation and axon extension beginning at basal cell division. In parallel, we mapped the molecular development of OSNs beginning at basal cell division, including the onset of OR expression. Our data show that ORs are first expressed around 4 d following basal cell division, 24 h after OSN axons have reached the OB. Over the next 6+ days the OSN axons navigate the OB nerve layer and ultimately coalesce in glomeruli. These data provide a previously unidentified perspective on the role of ORs in homophilic OSN axon adhesion and lead us to propose a new model dividing axon extension into two phases. Phase I is OR-independent and accounts for up to 50% of the time during which axons approach the OB and begin navigating the olfactory nerve layer. Phase II is OR-dependent and concludes as OSN axons coalesce in glomeruli.olfactory epithelium | axon guidance | tamoxifen | olfactory marker protein | Ascl1 I n the mouse olfactory system, olfactory sensory neurons (OSNs) extend their axons from the olfactory epithelium (OE) to the olfactory bulb (OB), where they converge to form glomeruli. Each OSN expresses only 1 of ∼2,400 candidate odorant receptor (OR) alleles. OSNs expressing the same OR can be widely dispersed in the OE, yet their axons converge in only two to three molecularly specific glomeruli of a possible 3,700 (1). It was first recognized almost 20 y ago that substituting an OR-coding region with that of a different OR resulted in the glomerular convergence of axons at an ectopic location relative to that of the native ORs (2). This led to the suggestion that ORs have an instructive role in the extension and glomerular coalescence of OSN axons, most likely mediated by homophilic fasciculation (3-5).Postnatal OSNs are derived from self-renewing precursors located proximal to the deep basal lamina of the OE (6). Following the division of globose basal stem cells, OSN neuroblasts transiently express Achaete-scute homolog 1 (Ascl1) followed by two phases of differentiation (6-8). Initially, they express growthassociated protein-43 (GAP-43), a marker of immature cells. Subsequently, the OSNs down-regulate GAP-43 and express olfactory marker protein (OMP), a universal marker of mature OSNs.Although there is a consensus on the involvement of ORs in OSN axon glomerular convergence, when ORs exert that influence following basal cell division or axon extension is not known. Moreover, the developmental progression of GAP-43 to OMP, as a measure of OSN differentiation and maturation, or of adenylate cyclase 3 (AC3), a downstream signaling molecule also implicated in axon extension, has not been considered in the context of OR expression or OSN dynamics. Here, we determined when ORs exert thei...

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“…[24][25][26] More recently it has been shown that the potassium-dependent Na C /Ca 2C exchanger 4 (NCKX4) is expressed in the cilia of OSNs and plays the major role in Ca 2C extrusion and therefore, in controlling the termination of the odorant response. [27][28][29] A further contribution to Ca 2C dynamics inside the cilia of OSNs is given by mitochondria in the dendritic knob. Not only do they contribute to the low resting Ca 2C but also they are responsible for its clearance during odorant stimulation.…”

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confidence: 99%

The long tale of the calcium activated Cl⁻channels in olfactory transduction

et al. 2017

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Ca 2C-activated Cl ¡ currents have been implicated in many cellular processes in different cells, but for many years, their molecular identity remained unknown. Particularly intriguing are Ca 2C -activated Cl ¡ currents in olfactory transduction, first described in the early 90s. Well characterized electrophysiologically, they carry most of the odorant-induced receptor current in the cilia of olfactory sensory neurons (OSNs). After many attempts to determine their molecular identity, TMEM16B was found to be abundantly expressed in the cilia of OSNs in 2009 and having biophysical properties like those of the native olfactory channel. A TMEM16B knockout mouse confirmed that TMEM16B was indeed the olfactory Cl ¡ channel but also suggested a limited role in olfactory physiology and behavior.The question then arises of what the precise role of TMEM16b in olfaction is. Here we review the long story of this channel and its possible roles.

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The Na+/Ca2+ exchanger NCKX4 governs termination and adaptation of the mammalian olfactory response

Cited by 108 publications

References 50 publications

The Odorant Receptor-Dependent Role of Olfactory Marker Protein in Olfactory Receptor Neurons

The Odorant Receptor-Dependent Role of Olfactory Marker Protein in Olfactory Receptor Neurons

Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons

The long tale of the calcium activated Cl⁻channels in olfactory transduction

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The Na+/Ca2+ exchanger NCKX4 governs termination and adaptation of the mammalian olfactory response

Cited by 108 publications

References 50 publications

The Odorant Receptor-Dependent Role of Olfactory Marker Protein in Olfactory Receptor Neurons

The Odorant Receptor-Dependent Role of Olfactory Marker Protein in Olfactory Receptor Neurons

Odorant receptors regulate the final glomerular coalescence of olfactory sensory neuron axons

The long tale of the calcium activated Cl−channels in olfactory transduction

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The long tale of the calcium activated Cl⁻channels in olfactory transduction