Ciliary Targeting of Olfactory CNG Channels Requires the CNGB1b Subunit and the Kinesin-2 Motor Protein, KIF17

Jenkins, Paul M.; Hurd, Toby W.; Zhang, Lian; McEwen, Dyke P.; Brown, R. Lane; Margolis, Ben; Verhey, Kristen J.; Martens, Jeffrey R.

doi:10.1016/j.cub.2006.04.034

Cited by 203 publications

(219 citation statements)

References 28 publications

(31 reference statements)

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“…In heteromeric channels containing CNGA2, CNGA4, and CNGB1b, PIP 3 and Ca 2ϩ ͞CaM produce distinct functional changes by binding to different subunits, yet PIP 3 still blocks Ca 2ϩ ͞CaM regulation. Our findings reaffirm the regulatory significance of the CNGA2 N terminus in the heteromeric channel and indicate that each subunit in native olfactory CNG channels has a distinct and important role in channel regulation and trafficking (28)(29)(30).…”

Section: Discussionsupporting

confidence: 75%

Interplay between PIP ₃ and calmodulin regulation of olfactory cyclic nucleotide-gated channels

Brady

Rich

Martens

et al. 2006

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

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Phosphatidylinositol-3,4,5-trisphosphate (PIP3) has been proposed to modulate the odorant sensitivity of olfactory sensory neurons by inhibiting activation of cyclic nucleotide-gated (CNG) channels in the cilia. When applied to the intracellular face of excised patches, PIP3 has been shown to inhibit activation of heteromeric olfactory CNG channels, composed of CNGA2, CNGA4, and CNGB1b subunits, and homomeric CNGA2 channels. In contrast, we discovered that channels formed by CNGA3 subunits from cone photoreceptors were unaffected by PIP3. Using chimeric channels and a deletion mutant, we determined that residues 61-90 within the N terminus of CNGA2 are necessary for PIP3 regulation, and a biochemical ''pulldown'' assay suggests that PIP3 directly binds this region. The N terminus of CNGA2 contains a previously identified calcium-calmodulin (Ca 2؉ ͞CaM)-binding domain (residues 68 -81) that mediates Ca 2؉ ͞CaM inhibition of homomeric CNGA2 channels but is functionally silent in heteromeric channels. We discovered, however, that this region is required for PIP3 regulation of both homomeric and heteromeric channels. Furthermore, PIP3 occluded the action of Ca 2؉ ͞CaM on both homomeric and heteromeric channels, in part by blocking Ca 2؉ ͞CaM binding. Our results establish the importance of the CNGA2 N terminus for PIP3 inhibition of olfactory CNG channels and suggest that PIP3 inhibits channel activation by disrupting an autoexcitatory interaction between the N and C termini of adjacent subunits. By dramatically suppressing channel currents, PIP3 may generate a shift in odorant sensitivity that does not require prior channel activity.lipid signaling ͉ olfaction ͉ phosphatidylinositide ͉ sensory adaptation O dorant binding to specialized receptors in the cilia of olfactory sensory neurons triggers an increase in intracellular cAMP (1-4), which directly opens cyclic nucleotide-gated (CNG) channels (5). Calcium influx through CNG channels activates an atypical chloride current (6-8), leading to depolarization of the cell membrane. The elevated calcium also causes rapid adaptation to odorants by triggering a calcium-calmodulin (Ca 2ϩ ͞CaM)-dependent decrease in the sensitivity of CNG channels to cAMP (9). Recent evidence suggests that phosphatidylinositol-3,4,5-trisphosphate (PIP 3 ) also decreases the sensitivity of olfactory CNG channels and reduces the response of olfactory sensory neurons to complex odors, but the mechanism has yet to be elucidated (10, 11).Ca 2ϩ ͞CaM inhibits homomeric CNGA2 channel activation by binding to a Baa-like motif in the N terminus (12-14), thereby disrupting an autostimulatory interaction with the C terminus of an adjacent subunit (15-17). Deletion of the Ca 2ϩ ͞CaM-binding domain (amino acids 68-81) in CNGA2 produces channels that are resistant to inhibition by Ca 2ϩ ͞CaM and exhibit dramatically reduced sensitivity to cyclic nucleotides due to the loss of the autostimulatory interaction. Native olfactory CNG channels are tetrameric assemblies of three different pore-forming subunits, C...

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Section: Discussionsupporting

confidence: 75%

Interplay between PIP ₃ and calmodulin regulation of olfactory cyclic nucleotide-gated channels

Brady

Rich

Martens

et al. 2006

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

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“…In vertebrates, the function of kif17 has been studied in tissue culture as well as in mouse and zebrafish models. Tissue culture studies provided evidence that kif17 is necessary for the transport of a cyclic nucleotide-gated channel subunit but not for the elongation of cilia (37), whereas the mouse KO analysis revealed a role in learning and memory (24). Our studies demonstrate a function for kif17 in the morphogenesis of a subset of vertebrate cilia.…”

Section: Discussionmentioning

confidence: 71%

Kinesin-2 family in vertebrate ciliogenesis

Zhao

Omori²,

Brodowska

et al. 2012

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

124

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The differentiation of cilia is mediated by kinesin-driven transport. As the function of kinesins in vertebrate ciliogenesis is poorly characterized, we decided to determine the role of kinesin-2 family motors-heterotrimeric kinesin-II and the homodimeric Kif17 kinesin-in zebrafish cilia. We report that kif17 is largely dispensable for ciliogenesis; kif17 homozygous mutant animals are viable and display subtle morphological defects of olfactory cilia only. In contrast to that, the kif3b gene, encoding a heterotrimeric kinesin subunit, is necessary for cilia differentiation in most tissues, although exceptions exist, and include photoreceptors and a subset of hair cells. Cilia of these cell types persist even in kif3b/kif17 double mutants. Although we have not observed a functional redundancy of kif3b and kif17, kif17 is able to substitute for kif3b in some cilia. In contrast to kif3b/kif17 double mutants, simultaneous interference with kif3b and kif3c leads to the complete loss of photoreceptor and hair cell cilia, revealing redundancy of function. This is in agreement with the idea that Kif3b and Kif3c motor subunits form complexes with Kif3a, but not with each other. Interestingly, kif3b mutant photoreceptor cilia differentiate with a delay, suggesting that kif3c, although redundant with kif3b at later stages of differentiation, is not active early in photoreceptor ciliogenesis. Consistent with that, the overexpression of kif3c in kif3b mutants rescues early photoreceptor cilia defects. These data reveal unexpected diversity of functional relationships between vertebrate ciliary kinesins, and show that the repertoire of kinesin motors changes in some cilia during their differentiation. intraflagellar transport | opsin | outer segment | ciliary axoneme

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“…Several studies have identified cilia targeting domains. This has been done for polycystin-2 and the odorant responsive cyclic nucleotidegated channel CNGB1b, both of which require a RVXP motif for cilia localization (37,38). However, analysis of several other cilia transmembrane proteins indicates that the RVXP motif is not a universal targeting address (34,(37)(38)(39)(40).…”

Section: Cilia Architecturementioning

confidence: 99%

Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease

Yoder¹

2007

Journal of the American Society of Nephrology

257

221

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Cysts in the kidney are among the most common inherited human pathologies, and recent research has uncovered that a defect in cilia-mediated signaling activity is a key factor that leads to cyst formation. The cilium is a microtubule-based organelle that is found on most cells in the mammalian body. Multiple proteins whose functions are disrupted in cystic diseases have now been localized to the cilium or at the basal body at the base of the cilium. Current data indicate that the cilium can function as a mechanosensor to detect fluid flow through the lumen of renal tubules. Flow-mediated deflection of the cilia axoneme induces an increase in intracellular calcium and alters gene expression. Alternatively, a recent finding has revealed that the intraflagellar transport 88/polaris protein, which is required for cilia assembly, has an additional role in regulating cell-cycle progression independent of its function in ciliogenesis. Further research directed at understanding the relationship between the cilium, cell-cycle, and cilia-mediated mechanosensation and signaling activity will hopefully provide important insights into the mechanisms of renal cyst pathogenesis and lead to better approaches for therapeutic intervention.

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Ciliary Targeting of Olfactory CNG Channels Requires the CNGB1b Subunit and the Kinesin-2 Motor Protein, KIF17

Cited by 203 publications

References 28 publications

Interplay between PIP ₃ and calmodulin regulation of olfactory cyclic nucleotide-gated channels

Interplay between PIP ₃ and calmodulin regulation of olfactory cyclic nucleotide-gated channels

Kinesin-2 family in vertebrate ciliogenesis

Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease

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Ciliary Targeting of Olfactory CNG Channels Requires the CNGB1b Subunit and the Kinesin-2 Motor Protein, KIF17

Cited by 203 publications

References 28 publications

Interplay between PIP 3 and calmodulin regulation of olfactory cyclic nucleotide-gated channels

Interplay between PIP 3 and calmodulin regulation of olfactory cyclic nucleotide-gated channels

Kinesin-2 family in vertebrate ciliogenesis

Role of Primary Cilia in the Pathogenesis of Polycystic Kidney Disease

Contact Info

Product

Resources

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Interplay between PIP ₃ and calmodulin regulation of olfactory cyclic nucleotide-gated channels

Interplay between PIP ₃ and calmodulin regulation of olfactory cyclic nucleotide-gated channels