Lipid signaling to membrane proteins: From second messengers to membrane domains and adapter-free endocytosis

Hilgemann, Donald W.; Dai, Gucan; Collins, A. J.; Lariccia, Vincenzo; Magi, Simona; Deisl, Christine; Fine, Michael

doi:10.1085/jgp.201711875

Cited by 56 publications

(55 citation statements)

References 166 publications

(158 reference statements)

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“…Regarding the decrease in the exchanger reverse-mode activity, several mechanisms may come into play, including the removal of the exchanger from the extracellular surface by endocytic pathways 47 , 48 and the compensatory action possibly taking place among the different isoforms 49 . Nevertheless, the increase in the intracellular ATP levels induced by glutamate ultimately represents an upstream signal that tends to restore the overall cellular homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

et al. 2018

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In brain ischemia, reduction in oxygen and substrates affects mitochondrial respiratory chain and aerobic metabolism, culminating in ATP production impairment, ionic imbalance, and cell death. The restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury, giving rise to ischemia/reperfusion (I/R) injury. In this setting, the imbalance of brain bioenergetics induces important metabolic adaptations, including utilization of alternative energy sources, such as glutamate. Although glutamate has long been considered as a neurotoxin, it can also be used as intermediary metabolite for ATP synthesis, and both the Na+/Ca2+ exchanger (NCX) and the Na+-dependent excitatory amino-acid transporters (EAATs) are essential in this pathway. Here we analyzed the role of NCX in the potential of glutamate to improve metabolism and survival of neuronal cells subjected to hypoxia/reoxygenation (H/R). In SH-SY5Y neuroblastoma cells differentiated into a neuron-like state, H/R produced a significant cell damage, a decrease in ATP cellular content, and intracellular Ca2+ alterations. Exposure to glutamate at the onset of the reoxygenation phase attenuated H/R-induced cell damage and evoked a significant raise in intracellular ATP levels. Furthermore, we found that in H/R cells NCX reverse-mode activity was reduced, and that glutamate limited such reduction. All the effects induced by glutamate supplementation were lost when cells were transfected with small interfering RNA against NCX1 and EAAT3, suggesting the need of a specific functional interplay between these proteins for glutamate-induced protection. Collectively, our results revealed the potential beneficial effect of glutamate in an in vitro model of H/R injury and focused on the essential role exerted by NCX1. Although preliminary, these findings could be a starting point to further investigate in in vivo systems such protective effect in ischemic settings, shedding a new light on the classical view of glutamate as detrimental factor.

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Section: Discussionmentioning

confidence: 99%

Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

et al. 2018

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“…Despite these advances, our knowledge regarding the regulation of AKT2 remains relatively limited, and phospholipids may be neglected. In addition to functioning as membrane components, several kinds of phospholipids have been fully proved to be involved in gating K + channels in animal cells (Poveda et al , 2017; Hilgemann et al , 2018). Some phospholipids can act as second messengers by binding to specific sites that control channel gating, whereas other phospholipids act non‐specifically by modifying the physical membrane environment of the channels (Hilgemann et al , 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to functioning as membrane components, several kinds of phospholipids have been fully proved to be involved in gating K + channels in animal cells (Poveda et al , 2017; Hilgemann et al , 2018). Some phospholipids can act as second messengers by binding to specific sites that control channel gating, whereas other phospholipids act non‐specifically by modifying the physical membrane environment of the channels (Hilgemann et al , 2018). Among the phospholipid modulators, phosphatidylinositol bisphosphate (PIP 2 ) is the most studied lipid modulator of K + channels in animal cells (Suh and Hille, 2008).…”

Section: Introductionmentioning

confidence: 99%

Phosphatidic acid directly binds with rice potassium channel OsAKT2 to inhibit its activity

et al. 2020

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The plant Shaker K + channel AtAKT2 has been identified as a weakly rectifying channel that can stabilize membrane potentials to promote photoassimilate phloem loading and translocation. Thus, studies on functional characterization and regulatory mechanisms of AtAKT2-like channels in crops are highly important for improving crop production. Here, we identified the rice OsAKT2 as the ortholog of Arabidopsis AtAKT2, which is primarily expressed in the shoot phloem and localized at the plasma membrane. Using an electrophysiological assay, we found that OsAKT2 operated as a weakly rectifying K + channel, preventing H + /sucrose-symport-induced membrane depolarization. Three critical amino acid residues (K193, N206, and S326) are essential to the phosphorylation-mediated gating change of OsAKT2, consistent with the roles of the corresponding sites in AtAKT2. Disruption of OsAKT2 results in delayed growth of rice seedlings under short-day conditions. Interestingly, the lipid second messenger phosphatidic acid (PA) inhibits OsAKT2-mediated currents (both instantaneous and time-dependent components). Lipid dot-blot assay and liposomeprotein binding analysis revealed that PA directly bound with two adjacent arginine residues in the ANK domain of OsAKT2, which is essential to PA-mediated inhibition of OsAKT2. Electrophysiological and phenotypic analyses also showed the PA-mediated inhibition of AtAKT2 and the negative correlation between intrinsic PA level and Arabidopsis growth, suggesting that PA may inhibit AKT2 function to affect plant growth and development. Our results functionally characterize the Shaker K + channel OsAKT2 and reveal a direct link between phospholipid signaling and plant K + channel modulation.

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“…Since PIP2 and PIP3 have been implicated in regulation of vast array of proteins including ion channels and transporters (Hille et al, 2015;Hilgemann et al, 2018), we hypothesized that redistribution of PIP2 in OSN cilia of INPP5E-OMP KO would affect its ability to transduce odor. Surprisingly, we found only a weak phenotype resulting in acceleration of odor response.…”

Section: Discussionmentioning

confidence: 99%

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

Ukhanov

Uytingco

Green

et al. 2018

Preprint

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Ciliopathies manifested in part by a dysfunction of several phosphoinositide 5'phosphatases constitute Lowes, Dent disease 2 and Joubert syndromes through critical involvement of properly functioning primary cilia (PC). We showed that deletion of INPP5E under the control of OMP-Cre in mature mouse olfactory sensory neurons (OSNs) led to a dramatic redistribution of PI(4,5)P2 (PIP2) in cilia, significant reduction of PI(3,4)P2 and enrichment of PI(3,4,5)P3 in knobs.Redistribution of the phospholipids accompanied marked elongation of cilia in INPP5E-OMP knockout (KO) OSNs. Such a dramatic remodeling of phospholipid composition however did not affect other integral membrane lipids (cholesterol, sphingomyelin, glycosylated phosphaditylinositol, phosphatidylserine). Proteins known to bind with high affinity PIP2 entered the cilia of the KO OSNs. Loss of INPP5E did not affect ciliary localization of endogenous olfactory receptor M71/M72 or distribution and movement of IFT122 particles implicating independent of phospholipids mechanism of retrograde protein transport in cilia of mature OSNs. Net odor sensitivity and response magnitude as measured by EOG was not affected by the mutation.However, odor adaptation in the KO mouse was significantly impaired resulting in less efficient recovery and altered inactivation kinetics of the odor response at the EOG and single-cell level.These findings implicate phosphoinositide-dependent regulation of active Ca 2+ extrusion in OSNs whereby controlling the rate of sensory adaptation. Significance statementCurrently there are little if any available treatment to cure congenital ciliopathies. This is in part due to lack of basic knowledge of cilia biology. Olfactory cilia as well as primary cilia appear to be a phospholipid privileged organelle distinct from the rest of plasma membrane albeit sharing its continuity. We characterized distribution of several critically important for cell biology phospholipids and showed that their balance, especially of PIP2, is disrupted in Joubert syndrome animal model and has functional implications. Virally assisted delivery of wild type INPP5E to the mutant OSNs was able to restore localization of PIP2 and rescued impaired response to odor.

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Lipid signaling to membrane proteins: From second messengers to membrane domains and adapter-free endocytosis

Abstract: Hilgemann et al. explain how lipid signaling to membrane proteins involves a hierarchy of mechanisms from lipid binding to membrane domain coalescence.

Cited by 56 publications

References 166 publications

Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

Glutamate as a potential “survival factor” in an in vitro model of neuronal hypoxia/reoxygenation injury: leading role of the Na+/Ca2+ exchanger

Phosphatidic acid directly binds with rice potassium channel OsAKT2 to inhibit its activity

INPP5E controls ciliary localization of phospholipids and odor response kinetics in a mouse model of Joubert syndrome

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