Structural Biochemistry/LPA Receptors

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

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: G_αi/0, G_αq/11, and G_α12/13. 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

LPA₂ is a high affinity cognate LPA receptor. It couples to the G proteins G_αi/0, G_αq/11, and G_α12/13. 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 G_{α12/13/ 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

LPA₃ also couples with G_αi/0 and G_αq 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 G_α12/13 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

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

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 LPA_1-4 belong to the rhodopsin-GPCR family and is structurally different from LPA_1-3. The stress fiber formation and neurite retraction in LPA₅ expressing cells are induced by LPA by coupling to G_α12/13. It increases intracellular calcium levels by activating G_αq. 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 LPA_1-5 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.

References

1. Neil A. Campbell, Jane B. Reece "Biology 8th edition"
2. Woong Choi, Ji. D.R. Herr ect. "LPA Receptors: Subtypes and Biological Actions" Annu. Rev. Pharmacol. Toxicol. 2010. 50:157-86
3. Woong Choi, Ji. Jerold Chun. "Lysophospholipids and Their Receptors in the Central Nervous System" Biochimica et Biophysica Acta 2012

LPA Receptors

LPA1

LPA2

LPA3

LPA4

LPA5