Alternative Splicing Governs Cone Cyclic Nucleotide-gated (CNG) Channel Sensitivity to Regulation by Phosphoinositides

Dai, Gucan; Lama-Sherpa, Tshering; Varnum, Michael D.

doi:10.1074/jbc.m114.562272

Cited by 8 publications

(7 citation statements)

References 52 publications

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“…Our study further show that the (ac) and (a) isotypes of TMEM16A present different PI(4,5)P 2 sensitivity and that a single mutation of a lysine (K) residue in the c-segment suffices to remove the PI(4,5)P 2 -mediated TMEM16A(ac) regulation in the presence of ATP. Similar differential phosphoinositide regulation dependent on a channel's alternative splicing was previously reported in cyclic nucleotide-gated (CNG) channels, where inclusion of CNGA3 exon3 endows outstandingly potentiated sensitivity to PI(4,5)P 2 and PI(3,4,5)P 3 (42). Because the alternative exons of TMEM16A are spliced in a tissue-specific manner (5), the sensitivity to PI(4,5)P 2 should differ in different tissues.…”

Section: Discussionsupporting

confidence: 61%

Allosteric modulation of alternatively spliced Ca²⁺-activated Cl⁻channels TMEM16A by PI(4,5)P₂and CaMKII

Jung

Kim

et al. 2020

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

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Transmembrane 16A (TMEM16A, anoctamin1), 1 of 10 TMEM16 family proteins, is a Cl−channel activated by intracellular Ca2+and membrane voltage. This channel is also regulated by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. We find that two splice variants of TMEM16A show different sensitivity to endogenous PI(4,5)P2degradation, where TMEM16A(ac) displays higher channel activity and more current inhibition by PI(4,5)P2depletion than TMEM16A(a). These two channel isoforms differ in the alternative splicing of the c-segment (exon 13). The current amplitude and PI(4,5)P2sensitivity of both TMEM16A(ac) and (a) are significantly strengthened by decreased free cytosolic ATP and by conditions that decrease phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaMKII). Noise analysis suggests that the augmentation of currents is due to a rise of single-channel current (i), but not of channel number (N) or open probability (PO). Mutagenesis points to arginine 486 in the first intracellular loop as a putative binding site for PI(4,5)P2, and to serine 673 in the third intracellular loop as a site for regulatory channel phosphorylation that modulates the action of PI(4,5)P2. In silico simulation suggests how phosphorylation of S673 allosterically and differently changes the structure of the distant PI(4,5)P2-binding site between channel splice variants with and without the c-segment exon. In sum, our study reveals the following: differential regulation of alternatively spliced TMEM16A(ac) and (a) by plasma membrane PI(4,5)P2, modification of these effects by channel phosphorylation, identification of the molecular sites, and mechanistic explanation by in silico simulation.

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Section: Discussionsupporting

confidence: 61%

Allosteric modulation of alternatively spliced Ca²⁺-activated Cl⁻channels TMEM16A by PI(4,5)P₂and CaMKII

Jung

Kim

et al. 2020

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

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“…The first is the cyclic nucleotide gated CNG family, channels that are opened by intracellular ATP or GTP. CNG channels of photoreceptors (cones and rods) and olfactory neurons require more cyclic nucleotide to be activated when levels of PI(4,5)P 2 or PI(3,4,5)P 3 increase [118-122]. The sensitivity to PI(4,5)P 2 varies with the specific channel subtype, being low for olfactory channels, as well as with the splice variant expressed.…”

Section: Other Plasma Membrane Channels Regulated By Phosphoinositmentioning

confidence: 99%

Phosphoinositides regulate ion channels

Hille

Dickson

Kruse

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

276

278

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Phosphoinositides serve as signature motifs for different cellular membranes and often are required for the function of membrane proteins. Here, we summarize clear evidence supporting the concept that many ion channels are regulated by membrane phosphoinositides. We describe tools used to test their dependence on phosphoinositides, especially phosphatidylinositol 4,5-bisphosphate, and consider mechanisms and biological meanings of phosphoinositide regulation of ion channels. This lipid regulation can underlie changes of channel activity and electrical excitability in response to receptors. Since different intracellular membranes have different lipid compositions, the activity of ion channels still in transit towards their final destination membrane may be suppressed until they reach an optimal lipid environment.

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“…As the uterine arteries from Rln −/− mice no longer demonstrated a reduced sensitivity to ACh during late pregnancy in the absence of inhibitors, this may be due to an increase in ACh receptor expression. Of the novel genes influenced by relaxin deficiency Cnga3 , a cyclic nucleotide gated channel subunit, is involved in signal transduction and can be influenced by calcium ions (Dai et al, 2014 ), making it an interesting find. The hypoxia-inducing factor α ( Hif1 α), a subunit of a hypoxia acting transcription factor (Benita et al, 2009 ) was downregulated in the uterine artery of late pregnant Rln −/− mice.…”

Section: Discussionmentioning

confidence: 99%

Relaxin Deficiency Leads to Uterine Artery Dysfunction During Pregnancy in Mice

et al. 2018

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The uterine vasculature undergoes profound adaptations in response to pregnancy. Augmentation of endothelial vasodilator function and reduced smooth muscle reactivity are factors contributing to uterine artery adaptation and are critical for adequate placental perfusion. The peptide hormone relaxin has an important role in mediating the normal maternal renal vascular adaptations during pregnancy through a reduction in myogenic tone and an increase in flow-mediated vasodilation. Little is known however about the influence of endogenous relaxin on the uterine artery during pregnancy. We tested the hypothesis that relaxin deficiency increases myogenic tone and impairs endothelial vasodilator function in uterine arteries of late pregnant relaxin deficient (Rln−/−) mice. Reactivity of main uterine arteries from non-pregnant and late pregnant wild-type (Rln+/+) and Rln−/− mice was studied using pressure and wire myography and changes in gene expression explored using PCR. Myogenic tone was indistinguishable in arteries from non-pregnant mice. In late pregnancy uterine artery myogenic tone was halved in Rln+/+ mice (P < 0.0001), an adaptation that failed to occur in arteries from pregnant Rln−/− mice. The role of vasodilator prostanoids in the regulation of myogenic tone was significantly reduced in arteries of pregnant Rln−/− mice (P = 0.02). Agonist-mediated endothelium-dependent vasodilation was significantly impaired in non-pregnant Rln−/− mice. With pregnancy, differences in total endothelial vasodilator function were resolved, although there remained an underlying deficiency in the role of vasodilator prostanoids and alterations to the contributions of calcium-activated K+ channels. Fetuses of late pregnant Rln−/− mice were ~10% lighter (P < 0.001) than those of Rln+/+ mice. In conclusion, relaxin deficiency is associated with failed suppression of uterine artery myogenic tone in pregnancy, which likely contributes to reduced uteroplacental perfusion and fetal growth restriction.

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Alternative Splicing Governs Cone Cyclic Nucleotide-gated (CNG) Channel Sensitivity to Regulation by Phosphoinositides

Cited by 8 publications

References 52 publications

Allosteric modulation of alternatively spliced Ca²⁺-activated Cl⁻channels TMEM16A by PI(4,5)P₂and CaMKII

Allosteric modulation of alternatively spliced Ca²⁺-activated Cl⁻channels TMEM16A by PI(4,5)P₂and CaMKII

Phosphoinositides regulate ion channels

Relaxin Deficiency Leads to Uterine Artery Dysfunction During Pregnancy in Mice

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Alternative Splicing Governs Cone Cyclic Nucleotide-gated (CNG) Channel Sensitivity to Regulation by Phosphoinositides

Cited by 8 publications

References 52 publications

Allosteric modulation of alternatively spliced Ca2+-activated Cl−channels TMEM16A by PI(4,5)P2and CaMKII

Allosteric modulation of alternatively spliced Ca2+-activated Cl−channels TMEM16A by PI(4,5)P2and CaMKII

Phosphoinositides regulate ion channels

Relaxin Deficiency Leads to Uterine Artery Dysfunction During Pregnancy in Mice

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Product

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Allosteric modulation of alternatively spliced Ca²⁺-activated Cl⁻channels TMEM16A by PI(4,5)P₂and CaMKII

Allosteric modulation of alternatively spliced Ca²⁺-activated Cl⁻channels TMEM16A by PI(4,5)P₂and CaMKII