Do Phosphatidylinositides Modulate Vertebrate Phototransduction?

Womack, Kyle; Gordon, Sharona E.; He, Feng; Wensel, Theodore G.; Lu, Chin Chi; Hilgemann, Donald W.

doi:10.1523/jneurosci.20-08-02792.2000

Cited by 80 publications

(60 citation statements)

References 40 publications

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“…Phosphatidylinositol 4,5-bisphosphate inhibition of sea urchin HCN channels (34) and ELK channels of the KCNH family (35) is thought to occur via the proximal AЈ helix. CNG channels have also been shown to be inhibited by phosphatidylinositol 4,5-bisphosphate (36), and it is possible that the AЈ helix is involved in this regulation. These studies indicate that the AЈ helix is a strong modulator of gating in the cyclic nucleotide-regulated channel family, and may be an important site for channel regulation in photoreceptors, olfactory receptors, and other neurons.…”

Section: Discussionmentioning

confidence: 99%

Regulation of CNGA1 Channel Gating by Interactions with the Membrane

Aman

Gordon

Zagotta

2016

Journal of Biological Chemistry

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Cyclic nucleotide-gated (CNG) channels are expressed in rod photoreceptors and open in response to direct binding of cyclic nucleotides. We have previously shown that potentiation of CNGA1 channels by transition metals requires a histidine in the A helix following the S6 transmembrane segment. Here, we used transition metal ion FRET and patch clamp fluorometry with a fluorescent, noncanonical amino acid (3-(6-acetylnaphthalen-2-ylamino)-2-aminopropanoic acid (Anap)) to show that the potentiating transition metal Co 2؉ binds in or near the A helix. Adding high-affinity metal-binding sites to the membrane (stearoyl-nitrilotriacetic acid (C18-NTA)) increased potentiation for low Co 2؉ concentrations, indicating that the membrane can coordinate metal ions with the A helix. These results suggest that restraining the A helix to the plasma membrane potentiates CNGA1 channel opening. Similar interactions between the A helix and the plasma membrane may underlie regulation of structurally related hyperpolarizationactivated cyclic nucleotide-gated (HCN) and voltage-gated potassium subfamily H (KCNH) channels by plasma membrane components. Cyclic nucleotide-gated (CNG)2 channels are voltage-independent, nonselective cation channels that are activated by the direct binding of cGMP and cAMP (1, 2). They are expressed in photoreceptors and olfactory receptors, where they mediate visual and olfactory transduction, respectively (3). They are also expressed throughout the brain (4, 5), where they can modulate neuronal excitability (6) and long-term potentiation (7). CNG channels are structurally similar to hyperpolarization-activated cyclic nucleotide-gated (HCN) and voltage-gated potassium subfamily H (KCNH) channels (1, 8). They are composed of four subunits forming around the central ion-conducting pore (Fig. 1A). Each subunit has a C-terminal cyclic nucleotide-binding domain (CNBD), which is connected to the channel pore by a C-linker region (Fig. 1B) (9). In CNG and HCN channels, cyclic nucleotide binding to the CNBD causes a conformational change in the C-linker, which then favors opening of the channel pore.Although structural rearrangements of the CNBD have been extensively studied, rearrangements of the C-linker are less well understood. The C-linker is the site of virtually all of the intersubunit interactions in the C-terminal region. It is composed of several ␣ helices, the most N-terminal of which is the AЈ helix, directly following the S6 transmembrane segment (Fig. 1B) (9). Based on the structure of the isolated C-linker and CNBD of HCN2, the AЈ helix is thought to run nearly parallel to the membrane near the cytosolic surface.The first evidence that the AЈ helix plays a role in channel gating came from studies of transition metal ion effects on CNGA1 (rod) and CNGA2 (olfactory) channels. Micromolar concentrations of transition metals were found to potentiate activation of rod channels, increasing the currents in response to partial agonists and subsaturating concentrations of full agonists (10 -12). This effect wa...

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Section: Discussionmentioning

confidence: 99%

Regulation of CNGA1 Channel Gating by Interactions with the Membrane

Aman

Gordon

Zagotta

2016

Journal of Biological Chemistry

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“…PI-4,5-P 2 can activate phosphodiesterase, which results in the inhibition of current fl ow through cyclic nucleotide-gated channels in ROSs ( 240 ). Modulation of phototransduction gain by changes in PI levels has been reported ( 241 ).…”

Section: Phosphoinositides In Retina Structure and Functionmentioning

confidence: 99%

Phosphoinositide 3-kinase signaling in the vertebrate retina

Rajala

2010

Journal of Lipid Research

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This article is available online at http://www.jlr.org was established by Streb et al. ( 3 ) in their classic paper that showed elevations in IP 3 caused intracellular release of bound calcium. Subsequently, 1,2-DG was found to stimulate protein kinase C (PKC), a serine/threonine kinase that phosphorylates a number of cellular proteins ( 4 ). Activation of the PLC/PKC cascade affects a variety of cellular events, including secretion, phagocytosis, smooth muscle contraction, proliferation, neurotransmission, and metabolism [see reviews by Rhee ( 5 ), Rhee and Choi ( 6 ), and Berridge ( 7 ) THE PI CYCLEIn the early 1950s, Hokin and Hokin ( 1, 2 ) discovered that addition of acetylcholine to brain slices stimulated the incorporation of phosphate and inositol but not glycerol into lipids; the major products of this incorporation were phosphatidylinositol (PI) and phosphatidic acid. Subsequent studies defi ned the reactions of the PI cycle and showed that the initial event was receptor-meditated activation of a phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PI-4,5-P 2 ) to 1,2-diacylglycerol (DG) and inositol 1,4,5-trisphosphate (IP 3 ). This increase in lipid synthesis reported by the Hokins was a recovery reaction that rapidly replenished PI separate from de novo PI synthesis. The role of 1,4, This work was supported by grants

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“…Activation of rod channels is reduced dramatically by application of diacylglycerol derivatives (22,23), all-trans-retinal (24), and phosphatidylinositol-4,5-bisphosphate (PIP 2 ) (25), and activation of olfactory CNG channels is inhibited by cholesterol depletion (26). Zhainazarov et al (11) reported that PIP 3 inhibits heterologously expressed CNGA2 homomeric channels or CNGA2͞CNGA4 heteromeric channels to nearly the same extent as native channels in olfactory sensory neuron membranes.…”

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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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Do Phosphatidylinositides Modulate Vertebrate Phototransduction?

Cited by 80 publications

References 40 publications

Regulation of CNGA1 Channel Gating by Interactions with the Membrane

Regulation of CNGA1 Channel Gating by Interactions with the Membrane

Phosphoinositide 3-kinase signaling in the vertebrate retina

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

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Do Phosphatidylinositides Modulate Vertebrate Phototransduction?

Cited by 80 publications

References 40 publications

Regulation of CNGA1 Channel Gating by Interactions with the Membrane

Regulation of CNGA1 Channel Gating by Interactions with the Membrane

Phosphoinositide 3-kinase signaling in the vertebrate retina

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

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