Structural Biochemistry/LPA Receptors
Lysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule by binding to and activating G protein-coupled receptors. There are about five known G protein-coupled receptors (GPCRs): LPA1, LPA2, LPA3, LPA4 and LPA5. LPA has diverse biological roles such as developmental, physiological, and pathophysiological effects.
LPA is a small glycerophospholipid present in low concentrations in all-eukaryotic tissues. It is present in high concentrations in blood plasma. LPA1 was the first high affinity, cognate cell surface receptor identified which then led to the identification of similar receptors LPA2 and LPA3 and divergent receptors LPA4 and LPA5. All five of these receptors are type 1 GPCRs, which differ in tissue distribution and downstream signaling pathways. The effects of LPA at physiological concentrations are mediated by these five receptors. In the brain for example, LPA1, LPA2 and LPA4 are expressed in developing brain and LPA3 is expressed in the postnatal brain. Expression of LPA1 and LPA2 can also be found in neurons.
LPA1 was discovered in the embryonic ventricular zone and shows high gene expression in this region. LPA1 couples and activates three types of G proteins: Gαi/0, Gαq/11, and Gα12/13. The activation of LPA1 prompts many cellular responses such as cell proliferation and survival, cell migration, and cytoskeletal changes. It also plays a role in altered cell-cell contact through serum response element activation as well as Ca2+ mobilization.
LPA2 is a high affinity cognate LPA receptor. It couples to the G proteins Gαi/0, Gαq/11, and Gα12/13. These G proteins carry signals through downstream molecules such as Ras (monomeric GTP-binding protein), mitogen-activated protein activated protein kinase, phosphatidylinositol 3 Kinase, Rac (small GTP-binding protein), phospholipase, diacylglycerol, and Rho, which is comparable to LPA1.
Activation of LPA2 signaling is associated with cell survival and cell migration. LPA2 promotes cell migration through interfaces with focal adhesion molecule TRIP6 and several PDZ proteins and zinc finger proteins, which work directly with the carboxyl-terminal tail of LPA2. It can also provide inhibitory effects on the epidermal growth factor, which induces migration and invasion of pancreatic cancer cells through the Gα12/13/ Rho pathway. LPA2 signaling has cross-regulation between classical G protein signaling cascades. It also has other signaling pathways that regulate the affinity and specificity of signal transduction.
LPA3 also couples with Gαi/0 and Gαq in order to mediate LPA induced phospholipase C activation, Ca2+ mobilization, adenylyl cyclase inhibition and activation, and mitogenactivated protein kinase activation. LPA3 does not couple with Gα12/13 and therefore does not mediate in neuronal cells. It also has a high affinity for 2-acyl-LPA containing unsaturated fatty acids. LPA3 is not as responsive as LPA1 and LPA2 are to LPA species with saturated acyl chains.
LPA4 is structurally different from classical LPA and is related to P2Y purinergic receptors. It does not respond to nucleotides or nucleosides. LPA4 has a suppressive effect on cell mobility in which deficiency in LPA4 enhances migratory response to LPA on fibroblast and heterologous expressions of LPA4. It also suppresses LPA1 dependent migration of B103 cells (neuroblastoma cells) and LPA induced migration and invasion of colon cancer cells.
Lpa5 is expressed in many parts of the body such as the brain and peripheral nervous system. LPA5 expression can be identified in sensory and motor neurons in the spinal cord and has a functional role in pain processing such as acute and neuropathic pain. LPA5 just like LPA1-4 belong to the rhodopsin-GPCR family and is structurally different from LPA1-3. The stress fiber formation and neurite retraction in LPA5 expressing cells are induced by LPA by coupling to Gα12/13. It increases intracellular calcium levels by activating Gαq. LPA is also responsible for the phosphate production and increased cAMP levels in LPA5 expressing cells. LPA5 is a LPA receptor that can be activated by farnesyl pyrophosphate at high concentrations.
LPA in the Nervous System
The central nervous system contains high LPA receptor expression. It is seen in various nervous system cell types such as neural progenitors, primary neurons, astrocytes, microglia, oligodendrocytes and Schwann cells. LPA signaling is also involved in developmental processes within the nervous system including cortical development and function, growth and folding of the cerebral cortex, survival, migration and proliferation.
Astrocytes for example, play an important role in neurodevelopmental and neurodegenerative processes and express all LPA receptors. Astrocytes are an abundant glial cell type in the central nervous system (CNS) that regulates biological and pathological processes. LPA signaling regulates morphological changes of astrocytes via the Rho-cAMP pathway and stabilization of stress fibers. LPA signaling is also related to neuronal differentiation, which is a function of astrocytes. LPA-primed astrocytes emit soluble factors to increase neuronal differentiation.
Schwann cells (SCs) are myelinating cells of the peripheral nervous system. They express LPA1 and LPA2 and their activation affect processes dealing with myelination. LPA mediates SC survival and prompts regulation of actin cytoskeleton and cellular adhesion properties
LPA in the Vascular System
The vascular system involves proliferation, migration, adhesion, differentiation, and assembly of vascular endothelial cells and vascular smooth muscle cells (VSMCs). LPA induces many responses in endothelial cells such as cell death, proliferation, migration and vasoconstriction. LPA induces cell death though protein nitrosylation (covalently adding a nitric oxide into a thiol group). LPA signaling in cardiovascular systems have been seen in hypotension and hypertension through vasoregulatory actions of LPA. LPA has many effects in VSMCs. It acts as a phenotypic modulator as atherosclerotic lesions develop. It responds to vascular injury by prompting the dedifferentiations (less specialized cell becomes a more specialized cell) of VSMCs. LPA also prompt the proliferation and migration of VSMCs.
LPA signaling and Neural Progenitor Cells
LPA signaling is involved in regulation of biological responses of neural progenitor cells (NPCs) by LPA receptors LPA1, LPA2 and LPA4. NPCs are involved in proliferation, morphogenesis, migration, apoptosis and differentiation, this is known as neurogenesis. The involvement of LPA receptors in NPCs has been revealed by heterologous expression studies that used cell lines in which single or multiple LPA receptors such as LPA1-5 were expressed. Studies that used NPCs, neurospheres, and ex vivo cultures have also showed the control of cell proliferation and differentiation through LPA1.
LPA and Diseases
LPA signaling is suspected to have a relationship with neurological diseases such as schizophrenia and autism. Some studies have compared prenatal fetal or maternal bleeding and other factors to autism and schizophrenia. Since LPA and its metabolic precursors are preset in blood it is probable that the exposure of LPA to the brain can occur through hemorrhage. This can lead to changes in the cerebral cortex related to observation in autism and schizophrenia. Conditions in which blood-brain barrier is compromised or the LPA production is altered can result in abnormal LPA signaling, which can lead to neurological pathologies.
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