Functional Conversion Between A-Type and Delayed Rectifier K
            <sup>+</sup>
            Channels by Membrane Lipids

Oliver, Dominik; Lien, Cheng Chang; Soom, Malle; Baukrowitz, Thomas; Jónás, Péter; Fakler, Bernd

doi:10.1126/science.1094113

Cited by 305 publications

(287 citation statements)

References 37 publications

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“…Because PIP 3 inhibition requires residues 61-90 and prevents Ca 2ϩ ͞CaM regulation, we postulate that PIP 3 binding may anchor the N terminus of CNGA2 to the membrane surface, thereby disrupting the intersubunit autostimulatory interaction. This molecular mechanism resembles that recently proposed for prevention of K ϩ channel N-type inactivation by phosphoinositides: sequestering of the Nterminal domain at the cytoplasmic face of the membrane (31). Although the N terminus of CNGA3 can bind both PIP 3 and Ca 2ϩ ͞CaM, these interactions appear to be functionally silent, most likely reflecting the absence of a pronounced autostimulatory interaction with the C terminus (27).…”

Section: Discussionmentioning

confidence: 79%

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: Discussionmentioning

confidence: 79%

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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“…Dashed lines represent standard errors of the mean (n ϭ 6). activity (41). We find that incubating rodent and human pancreatic islet ␤-cells with low micromolar concentrations of AA results in accelerated inactivation of their delayed rectifier Kvlike currents (Figs.…”

Section: Discussionmentioning

confidence: 98%

“…Arachidonic acid causes other slowly inactivating delayed rectifier K ϩ channels, such as Kv3.4, to resemble fast inactivating A-type K ϩ currents (41). The phospholipid content of esterified AA is higher in pancreatic islets than in other tissues (23,25,26,29), and arachidonate is hydrolyzed from phospholipids upon stimulation of islets with secretagogues (13,14,27,31,36,44) and accumulates to micromolar concentrations (7,27,28) that are sufficient to modulate delayed rectifier Kv channel FIGURE 5.…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

Jacobson

Weber

Bao

et al. 2007

Journal of Biological Chemistry

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Glucose stimulates both insulin secretion and hydrolysis of arachidonic acid (AA) esterified in membrane phospholipids of pancreatic islet ␤-cells, and these processes are amplified by muscarinic agonists. Here we demonstrate that nonesterified AA regulates the biophysical activity of the pancreatic islet ␤-cell-delayed rectifier channel, Kv2.1. Recordings of Kv2.1 currents from INS-1 insulinoma cells incubated with AA (5 M) and subjected to graded degrees of depolarization exhibit a significantly shorter time-to-peak current interval than do control cells. AA causes a rapid decay and reduced peak conductance of delayed rectifier currents from INS-1 cells and from primary ␤-cells isolated from mouse, rat, and human pancreatic islets. Stimulating mouse islets with AA results in a significant increase in the frequency of glucoseinduced [Ca 2؉ ] oscillations, which is an expected effect of Kv2.1 channel blockade. Stimulation with concentrations of glucose and carbachol that accelerate hydrolysis of endogenous AA from islet phosphoplipids also results in accelerated Kv2.1 inactivation and a shorter time-to-peak current interval. Group VIA phospholipase A 2 (iPLA 2 ␤) hydrolyzes ␤-cell membrane phospholipids to release nonesterified fatty acids, including AA, and inhibiting iPLA 2 ␤ prevents the muscarinic agonist-induced accelerated Kv2.1 inactivation. Furthermore, glucose and carbachol do not significantly affect Kv2.1 inactivation in ␤-cells from iPLA 2 ␤ ؊/؊ mice. Stably transfected INS-1 cells that overexpress iPLA 2 ␤ hydrolyze phospholipids more rapidly than control INS-1 cells and also exhibit an increase in the inactivation rate of the delayed rectifier currents. These results suggest that Kv2.1 currents could be dynamically modulated in the pancreatic islet ␤-cell by phospholipase-catalyzed hydrolysis of membrane phospholipids to yield non-esterified fatty acids, such as AA, that facilitate Ca 2؉ entry and insulin secretion.Glucose metabolism within the pancreatic islet ␤-cell generates a multitude of signals that regulate insulin secretion. Changes in the relative concentrations of the metabolites ATP and ADP cause ␤-cell depolarization via closure of ATP-sensitive potassium channels (K ATP ), 3 which results in activation of voltage-operated Ca 2ϩ channels, Ca 2ϩ influx, and insulin secretion (1). The extent of ␤-cell depolarization and insulin release are regulated in part by the activation of repolarizing ion channels, including the voltage-gated potassium channel, Kv2.1 (2-4). One mechanism employed by pancreatic ␤-cells to regulate the biophysical activity of the ion channels involved in insulin release involves hydrolysis of membrane phospholipids to yield mediators that include inositol triphosphates and free fatty acids (5-8).Pharmacologic, biochemical, and genetic evidence suggests that glucose-stimulated hydrolysis of esterified arachidonic acid from ␤-cell membrane phospholipids is required for physiological insulin secretion (7-25). Pancreatic islet ␤-cells contain high levels of arachidonic ac...

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“…As a result, the inactivation time constant of Kv␤1.1 was changed from Ͻ10 ms to a slow inactivation of hundreds of milliseconds. Oliver et al (33) recently also reported that membrane lipids can regulate inactivation of Kv1.1͞Kv␤1.1 by converting A-type channels into delayed rectifiers, and vice versa. The bidirectional control of Kv1.1͞Kv␤1.1 inactivation by lipids is mediated through immobilizing͞mobilizing the ␤ ball domain, suggesting a common mechanism for a dynamic regulation of neuronal excitability (33).…”

Section: Discussionmentioning

confidence: 99%

Functional coupling of intracellular calcium and inactivation of voltage-gated Kv1.1/Kvβ1.1 A-type K ⁺ channels

Jow

Zhang

Kopsco

et al. 2004

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

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Voltage-gated Kv1.1͞Kv␤1.1 A-type channels, as a natural complex, can switch from fast to slow inactivation under oxidation͞ reduction conditions. The mode-switching of inactivation, which is mediated by a cysteine residue in the inactivation ball domain of the Kv␤1.1 N terminus, can regulate membrane electrical excitability. In the present study, we identified a mechanism whereby inactivation in Kv1.1͞Kv␤1.1 channels is regulated by calcium influx. The rise in intracellular calcium, due to either influx from extracellular space or release from intracellular stores, eliminates fast inactivation induced by Kv␤1.1, resulting in slower inactivation and increased steady-state current. This oxidation-independent calcium effect is mediated through the Kv␤1.1 N terminus, not the C terminus. We propose that a coupling between calcium influx and inactivation of voltage-gated A-type K ؉ channels occurs as a result of membrane depolarization and may contribute to afterhyperpolarization as negative feedback to control neuronal excitability.calcium entry ͉ afterhyperpolarization ͉ Xenopus oocytes ͉ two-electrode voltage clamp

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Functional Conversion Between A-Type and Delayed Rectifier K ⁺ Channels by Membrane Lipids

Cited by 305 publications

References 37 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

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

Functional coupling of intracellular calcium and inactivation of voltage-gated Kv1.1/Kvβ1.1 A-type K ⁺ channels

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Functional Conversion Between A-Type and Delayed Rectifier K + Channels by Membrane Lipids

Cited by 305 publications

References 37 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

Modulation of the Pancreatic Islet β-Cell-delayed Rectifier Potassium Channel Kv2.1 by the Polyunsaturated Fatty Acid Arachidonate

Functional coupling of intracellular calcium and inactivation of voltage-gated Kv1.1/Kvβ1.1 A-type K + channels

Contact Info

Product

Resources

About

Functional Conversion Between A-Type and Delayed Rectifier K ⁺ Channels by Membrane Lipids

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

Functional coupling of intracellular calcium and inactivation of voltage-gated Kv1.1/Kvβ1.1 A-type K ⁺ channels