Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System
Abstract
:1. Introduction
2. Crosstalk between Neural Cells Regulates Cholesterol Homeostasis
2.1. Outline of the Brain Cholesterol Turnover
2.2. Brain Cholesterol Transporters
2.3. LDL Receptors
3. LDL Receptor Interactors in Normal and Pathological Brain Conditions
3.1. Reelin and F-Spondin
3.2. APP
3.3. Syntaxin 5 (Stx5), Selenoprotein P, Beclin 1 and NYGGF4
4. Influence of the Purinergic Signaling on the Main Functions of the Cholesterol Shuttle
4.1. Metabotropic P2 Receptors
4.2. Ionotropic P2 Receptors and Brain Cholesterol Turnover
4.3. Metabotropic P1 Receptors and Brain Cholesterol Turnover
4.4. Guanosine and Cholesterol Turnover
5. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Purine Receptors | |||
---|---|---|---|
P1 Receptors | P2 Receptors | ||
Receptor subtypes | Metabotropic receptors | Metabotropic P2Y receptors including | Ionotropic P2X receptors including |
A1, A2A, A2B, A3 | P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y14, P2Y14 | P2X1, P2X2, P2X3, P2X4, P2X5, P2X6, P2X7 | |
P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y14, P2Y14 | |||
Ligand(s) | Adenosine (ADO) | ATP, ADP, UTP, UDP | ATP |
Downstream effectors | Coupling to different types of G proteins and molecular pathways | Coupling to different types of G proteins and molecular pathways | Ion channels whose activation allows cation entry |
(A) Activities of purinergic receptors in relation to the brain “cholesterol shuttle” | |||
---|---|---|---|
Purine Signal | Cell Type | Activity on Cholesterol Shuttle and Related Dysregulation | Ref. |
P2Y1R | Immortalized APOE4 astrocytes | Increased Ca2+ excitability coupled to an altered lipidome pattern and intracellular cholesterol accumulation, possibly related to receptor hyperactivity. | [111] |
P2Y1R in cooperation with other P2YR (P2Y12R or P2Y13R) | Brain neural cells | To be explored in relation to a possible increase in the activity of neuronal ecto-F1-ATPase and ApoA-I uptake, similar to that observed in the liver or endothelial cells to assure the process known as “brain reverse cholesterol transport” (BRCT). | [118,119] |
P2Y2R | Human 1321N1 astrocytoma cells | Increased release of sAPPα deriving from the alpha- secretase activity. It should be investigated if this effect may provoke P2Y2R redistribution/internalization, as observed in peripheral cells. | [120,121] |
Rat cortical neurons upon IL1β stimulus | Receptor up-regulation coupled to an increased production of the protective sAPP alpha. | [122] | |
Rat cultured astrocytes | Receptor expression increased by cell stimulation with GUO, which also enhanced the UTP release from these cells, thus, contributing to the protective activity of astrocyte UTP/P2Y2R against AD risk. | [155] | |
P2X2R | CA1 hippocampal pyramidal cell/Schaffer collateral synapses | Interaction of the beta-amyloid precursor protein-binding protein Fe65 with the receptor at postsynaptic excitatory synapses, which resulted in receptor activity inhibition. | [127] |
P2X7R | Neural cells | Altered membrane lipid raft composition consequent to receptor stimulation. | [125] |
Increased ROS formation, which in turn, triggered Aβ peptide formation. | [131] | ||
Microglia | ATP release induced by Aβ1-42 peptide, which in turn, stimulated P2X7R -related ROS production. | [132] | |
Neural cells | P2X7R inhibition increased alpha-secretase activity, diminishing the number of amyloid plaques. | [134,135,136] | |
AD | Receptor polymorphisms. | [137] | |
A2AR | Fibroblasts from NPC1 patients as well as in human neuronal and oligoglial cell lines, in which NPC1 phenotype had been induced by siRNA | Receptor stimulation reduced the harmful intracellular accumulation of cholesterol as well as mitochondrial damage. | [144,145] |
Primary culture of oligodendrocyte progenitors | Receptor stimulation counteracted the cell maturation arrest induced by the inhibition of cholesterol transport and restored cell morphology. | [147] | |
Primary neuronal cells from AD mouse model | Istradefylline, a receptor antagonist, increased Aβ generation as well as A2AR KO-potentiated Aβ generation and gamma-secretase activity | [149] | |
(B) Influence of cholesterol turnover modifications on purinergic signals | |||
Cholesterol turnover alterations | Cell type | Modification of the purinergic signal | Ref. |
Membrane cholesterol depletion | Neural cells | Reduction of calcium currents induced by P2X2,4R stimulation, likely related to the expression of these receptors within membrane lipid rafts. | [125,126,127] |
Potentiated receptor activity caused by membrane cholesterol depletion as well as P2X7R stimulation. | [128] | ||
Reduction in membrane cholesterol levels | NCP1 cells | Impairment of normal A2AR activity with a decrease in cyclic adenosine monophosphate (cAMP) production. | [148] |
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Passarella, D.; Ronci, M.; Di Liberto, V.; Zuccarini, M.; Mudò, G.; Porcile, C.; Frinchi, M.; Di Iorio, P.; Ulrich, H.; Russo, C. Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System. Int. J. Mol. Sci. 2022, 23, 8683. https://doi.org/10.3390/ijms23158683
Passarella D, Ronci M, Di Liberto V, Zuccarini M, Mudò G, Porcile C, Frinchi M, Di Iorio P, Ulrich H, Russo C. Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System. International Journal of Molecular Sciences. 2022; 23(15):8683. https://doi.org/10.3390/ijms23158683
Chicago/Turabian StylePassarella, Daniela, Maurizio Ronci, Valentina Di Liberto, Mariachiara Zuccarini, Giuseppa Mudò, Carola Porcile, Monica Frinchi, Patrizia Di Iorio, Henning Ulrich, and Claudio Russo. 2022. "Bidirectional Control between Cholesterol Shuttle and Purine Signal at the Central Nervous System" International Journal of Molecular Sciences 23, no. 15: 8683. https://doi.org/10.3390/ijms23158683