Lysophosphatidic acid: receptors, signaling and survival

Swarthout, John T.; Walling, Hobart W.

doi:10.1007/pl00000678

Cited by 50 publications

(46 citation statements)

References 80 publications

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“…To assess the biochemical function of the mutant G␣ i2 , MEFs derived from wild-type, heterozygous, and homozygous littermate embryos were prepared. LPA inhibits AC and acts as a strong mitogen towards fibroblasts and other cell types via pertussis toxinsensitive processes (63). LPA-mediated inhibition of AC was measured in embryonic fibroblasts derived from both the homozygous and heterozygous mice ( Fig.…”

Section: G␣ I2mentioning

confidence: 99%

Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

Huang

Charbeneau

et al. 2006

Molecular and Cellular Biology

101

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Signal transduction via guanine nucleotide binding proteins (G proteins) is involved in cardiovascular, neural, endocrine, and immune cell function. Regulators of G protein signaling (RGS proteins) speed the turn-off of G protein signals and inhibit signal transduction, but the in vivo roles of RGS proteins remain poorly defined. To overcome the redundancy of RGS functions and reveal the total contribution of RGS regulation at the G␣ i2 subunit, we prepared a genomic knock-in of the RGS-insensitive G184S Gnai2 allele. The G␣ i2 G184S knock-in mice show a dramatic and complex phenotype affecting multiple organ systems (heart, myeloid, skeletal, and central nervous system). Both homozygotes and heterozygotes demonstrate reduced viability and decreased body weight. Other phenotypes include shortened long bones, a markedly enlarged spleen, elevated neutrophil counts, an enlarged heart, and behavioral hyperactivity. Heterozygous G␣ i2 ؉/G184S mice show some but not all of these abnormalities. Thus, loss of RGS actions at G␣ i2 produces a dramatic and pleiotropic phenotype which is more evident than the phenotype seen for individual RGS protein knockouts.Cell-cell communication is fundamental to the maintenance of homeostasis. The G protein-coupled receptor superfamily is arguably the most abundant and diverse protein family in cellular signaling and is tightly regulated. A novel family of Ͼ20 proteins termed regulators of G protein signaling, or RGS proteins, both tonically inhibit G protein function and also serve as signal control points (2,22,34,39,69). RGS-mediated inhibition of G protein signaling occurs through direct binding of the RGS protein to the G␣ subunit, with subsequent GTPase-accelerating protein (GAP) actions to rapidly deactivate G␣ (2). Deactivation may be accelerated up to 1,000-fold and shuts down both G␣ and G␤␥ signals (42, 48). RGS proteins may also competitively inhibit G␣ binding to effectors such as phospholipase C (32). Most of the currently known RGS proteins interact with either Gi or Gq family G proteins and influence cyclic AMP (cAMP), Ca 2ϩ , mitogen-activated protein kinase, and ion channel signaling. There is strong evidence implicating them in the subsecond kinetics of G i -and G o -mediated ion channel activation and deactivation in the heart (10, 21, 36) and neurons (36). In addition, the conserved RGS domain has been found to serve as a multifunctional protein adapter which can recruit many effectors or regulators to the vicinity of activated G proteins (31,53,62). Notable examples include p115rhoGEF (30, 40) and GRK2 (44). There is also emerging interest in RGS proteins as drug targets (9,20,53,72).However, the physiological functions of RGS proteins remain poorly defined. A number of RGS knockouts have been reported (for example, RGS1, -2, -4, and -9). The RGS9-1 knockout shows prolonged visual potentials (7), and RGS9-2 disruption results in markedly enhanced responses to drugs of abuse, such as cocaine, amphetamines, and opiates (56, 71). A human disorder, bradyopsia, with r...

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Section: G␣ I2mentioning

confidence: 99%

Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

Huang

Charbeneau

et al. 2006

Molecular and Cellular Biology

101

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“…Primary CLL Cells Express Higher Levels of LPA 1 Receptor Compared with Normal B-cells-LPA binds to four receptors, LPA [1][2][3][4] . LPA 1 is the most widely expressed receptor and is expressed in B-cells (3,17).…”

Section: Fig 3 Lpa Protects Primary Cll Cells Against Flu-induced Amentioning

confidence: 99%

“…Lysophosphatidic acid (LPA; 1-acyl-2-lyso-sn-glycero-3-phosphate) 1 is a naturally occurring soluble phospholipid that was initially identified as an intermediate in a de novo lipid biosynthesis pathway (1,2). LPA also possesses a range of biological activities similar to growth factors.…”

mentioning

confidence: 99%

“…LPA is present in the plasma bound to albumin (2). Similar to LPA receptors, LPA levels are often increased in ascites and the plasma of ovarian cancer patients and in the plasma of patients with multiple myeloma (1,15).…”

mentioning

confidence: 99%

“…Mice lacking LPA 1 show failure to suckle leading to neonatal mortality (19). In contrast, mice lacking LPA 2 show no obvious phenotypic deficiencies, indicating a redundancy in LPA receptor functionality (18). In addition, LPA 1 expression is increased in colon cancer cells, and LPA 2 and LPA 3 are elevated in ovarian cancer cells, suggesting that LPA receptors are involved in tumorigenesis (20,21).…”

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confidence: 99%

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Lysophosphatidic Acid (LPA) Protects Primary Chronic Lymphocytic Leukemia Cells from Apoptosis through LPA Receptor Activation of the Anti-apoptotic Protein AKT/PKB

Haney

Kropp

et al. 2005

Journal of Biological Chemistry

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Expression and function of calcium‐activated potassium channels in human glioma cells

Weaver

Bomben

Sontheimer

2006

Glia

142

151

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Ca(2+)-activated K(+) (K(Ca)) channels are a unique family of ion channels because they are capable of directly communicating calcium signals to changes in cell membrane potential required for cellular processes including but not limited to cellular proliferation and migration. It is now possible to distinguish three families of K(Ca) channels based on differences in their biophysical and pharmacological properties as well as genomic sequence. Using a combination of biochemical, molecular, and biophysical approaches, we show that human tumor cells of astrocytic origin, i.e. glioma cells, express transcripts for all three family members of K(Ca) channels including BK, IK, and all three SK channel types (SK1, SK2, and SK3). The use of selective pharmacological inhibitors shows prominent expression of currents that are inhibited by the BK channel specific inhibitors iberiotoxin and paxilline. However, despite the presence of transcripts for IK and SK, neither clotrimazole, an inhibitor of IK channels, nor apamin, known to block most SK channels inhibited any current. The exclusive expression of functional BK channels was further substantiated by shRNA knockdown experiments, which selectively reduced iberiotoxin sensitive currents. Western blotting of patient biopsies with antibodies specific for all three KCa channel types further substantiated the exclusive expression of BK type KCa channels in vivo. This finding is in sharp contrast to other cancers that express primarily IK channels.

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Lysophosphatidic acid: receptors, signaling and survival

Cited by 50 publications

References 80 publications

Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

Pleiotropic Phenotype of a Genomic Knock-In of an RGS-Insensitive G184S Gnai2 Allele

Lysophosphatidic Acid (LPA) Protects Primary Chronic Lymphocytic Leukemia Cells from Apoptosis through LPA Receptor Activation of the Anti-apoptotic Protein AKT/PKB

Expression and function of calcium‐activated potassium channels in human glioma cells

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