all-trans-Retinoic Acid Signaling in Brain
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all-trans-Retinoic Acid Signaling in Brain

Retinoic Acid, the active form of Vitamin-A (all-trans-Retinol), is a lipophilic molecule, and is known to affect gene transcription. Retinoic Acid is made available in the body through dietary intake and subsequent metabolism in the liver. Vitamin-A is secreted from its storage pools and circulates in blood. In the liver Vitamin-A is converted to all-trans-Retinoic acid, the Carboxylic Acid form of Vitamin-A and diffuses easily to the target tissues through cellular membranes; gets bound to CRABP (Cellular Retinoic Acid Binding Protein) and produces its biological effects through the activation of RARs (Retinoic Acid Receptors). Although biologically active ligands for the RARs also include 9-cis-Retinoic Acid among others, yet circulating levels of 9-cis-Retinoic Acid are much lower than those of all-trans-Retinoic Acid and  the physiological significance of the isomerization all-trans-Retinoic Acid to 9-cis-Retinoic Acid and vice versa  is yet to be ascertained. all-trans-Retinoic Acid modulates a wide variety of biological processes including Proliferation, Differentiation including Apoptosis and explains all of the biological effects of Vitamin-A (Ref.1). The capacity of Retinoic Acid to modulate gene transcription and expression is modulated not only by alterations in RBPs (Retinol-Binding Proteins)-mediated Retinoic Acid transport to target cells but also by the timing of exposure to Retinoic Acid and the spatial distribution of RARs in the target tissues. All of these factors markedly affect Retinoic Acid-mediated signaling in brain tissue also. The RARs are encoded by three separate genes from which multiple isoforms (Alpha, Beta and Gamma) are generated by alternative promoters and differential splicing. Like all NRs (Nuclear Receptors), the RARs are divided into six regions that is A-F, and have a conserved modular structure consisting of an AF-1 or A/B (Amino-Terminal Activating Factor-1 Transcriptional Activation) Domain; a zinc-finger DBD or C (DNA-Binding Domain); a CoR or D (Hinge/Corepressor Binding) Domain; a LBD or AF-2 or E (Ligand-Binding/Transcriptional Activation) Domain; and a variable F (Carboxyl-Terminal) Domain. The DBD binds to the RARE (Retinoic Acid Response Element) region in the DNA. The RAREs consists of a DRs (Direct Repeats) of AGG/TTCA motif with a spacer region of (n)25 (Ref. 2).

The molecular mechanism by which Retinoic Acid mediates Differentiation and Growth Suppression in neural cells remains unknown, however, all-trans-Retinoic Acid-induced release of Arachidonic Acid and its metabolites plays an important role. In brain tissue, Arachidonic Acid is mainly released by the action of PLA2 (Phospholipase-A2) Pathway (Ref.3). Phospholipids are the major lipid constituents of neural membranes as they provide neural membranes with Stability, Luidity, and Permeability. The neural membrane Phospholipids act as a reservoir for second messengers. Release of Arachidonic Acid by PLA2 and generation of Eicosanoids (Prostaglandins, Leukotrienes and Thromboxanes) are important metabolic processes that are associated with Cell Differentiation and Growth Suppression. Beside this all-trans-Retinoic Acid  also modulates inflammatory and immunological events including Cytokine signaling. Modulation of PLA2 activity by Cytokines and generation of Arachidonic Acid and its metabolites are central to inflammatory events that occur in brain tissue after traumatic and metabolic injuries. Multiple forms of PLA2 occur in brain. The PLA2 enzymes are subdivided into several groups depending upon their structure, enzymic properties, subcellular localization and cellular function. These isoforms include sPLA2 (Secretory Phospholipase-A2), cPLA2 (Cytosolic Phospholipase-A2), PlsEtn-PLA2 (Plasmalogen-Selective Phospholipase-A2), and iPLA2 (Calcium Independent Phospholipase-A2). The sPLA2, cPLA2 and iPLA2 occur in different regions of brain and in Astrocytes and are activated in response to all-trans-Retinoic Acid mediated RAR activation (Ref.3 & 4).

cPLA2 activity is regulated by translocation in the presence of Ca2+ (Calcium Ion) and by phosphorylation. Calcium mediates binding of the enzyme to Phospholipid substrate without being involved in the catalytic mechanism itself. An increase in the intracellular Ca2+ produces translocation of cPLA2 to nuclear membrane through a Ca2+ dependent lipid-binding motif. The translocation of cPLA2 from cytosol to nuclear membrane, brings cPLA2 into close proximity with other downstream enzymes like COX2 (Cyclooxygenase-2), PTGES (Prostaglandin-E Synthase), 5-LO (5-Lipoxygenase) and LTC4S (Leukotriene-C4 Synthase) that are responsible for the conversion of Arachidonic Acid into Prostaglandins and Leukotrienes (Ref.3).  In Astrocytes, cPLA2 converts Arachidonic Acid into PGH2 (Prostaglandin-H2) and then to PGE2 (Prostaglandin-E2) via the activation of COX2 and PTGES, respectively. Synergistic action of cPLA2, iPLA2 and 5-LO converts Arachidonic Acid into LTA4 (Leukotriene-A4) and further conversion of LTA4 to LTC4 (Leukotriene-C4) is catalyzed by LTC4S. The release hormone PGE2 and LTC4 control Differentiaton and Growth Suppression of brain cells. all-trans-Retinoic Acid  further accelerates the Acylation-Deacylation Cycle for maintenance of essential Phospholipids in the nuclear membrane (remodeling) via iPLA2 activation. This cycle protects the nuclear membrane from Lipid Peroxidation. The mechanism of all-trans-Retinoic Acid induced Apoptosis requires Cytokine-mediated stimulation of PLA2 activity, resulting in the generation of excess Arachidonic Acid (Ref.4).

all-trans-Retinoic Acid mediated PLA2 signaling is important for learning and memory. Dysregulation of all-trans-Retinoic Acid mediated PLA2 signaling may lead to Schizophrenia and Alzheimer Disease. Schizophrenia is a Chronic Psychiatric Disease with two major types of symptoms, Positive symptoms such as Hallucinations and Delusions, and Negative symptoms such as Amotivation, Apathy, and Asociality. Alzheimer Disease represents the most common cause of Senile Dementia (Ref.5). It is characterized by the accumulation of Neurofibrillary Tangles and Senile Plaques in the neocortex and hippocampus. At present, nothing is clear cut about the regulation of nuclear PLA2 activities. It is likely that pharmacological targeting of RARs by Retinoic Acid  analogs with diminished toxicity may alter the downstream expression of receptors involved in Schizophrenia and prevent Inflammation, Oxidative Stress, and Hamyloid Deposition in Alzheimer Disease. The discovery of Retinoic Acid analogs that can cross the Blood-Brain Barrier without causing any harm to the body tissues and normalize PLA2-mediated signaling are important for developing treatments for Schizophrenia and Alzheimers Disease (Ref.2).