Lysophosphatidic Acid-Induced Signals in Astrocytes

Abstract

Lysophosphatidic acid (LPA) is a potent lipid biomediator which evokes a broad array of responses in a diverse group of cell types (reviewed in Moolenaar, 1995; Tokumura, 1995). A sampling of LPA induced effects include stimulation of cell motility in cells ranging from Dictyostelium amoebae to monocytes, vasoactive responses, and platelet aggregation (Jalink et al., 1993; Zhou et al, 1995; Tokumura, 1995; Tokumura et al, 1981). The cell-type specificity of LPA-induced effects is illustrated by the LPA-induced stimulation of proliferation of cells, such as fibroblasts and myoblasts; inhibition of proliferation of some tumor cells; and stimulation of differentiation of keratinocytes (van Corven et al., 1989; Yoshida et al., 1996; Tigyi et al., 1994; Piazza et al., 1995). LPA stimulates many intracellular signal transduction pathways leading to an increase in the concentration of intracellular calcium ([Ca²⁺]_i), and stimulation of the activities of serine/threonine protein kinases, tyrosine kinases and phospholipases (e.g., Jalink et al., 1995; Amano et al., 1996; Howe and Marshall, 1993; van Corven et al., 1989; Ha et al., 1994). One LPA signal transduction pathway involves the small G protein rho since ADP-ribosylation of rho by Clostridium botulinum C3 exoenzyme inhibits some LPA-induced signals (Kumagai et al., 1993). Information about the cells and stimuli which induce the formation of LPA is limited, although it is well established that platelets produce LPA (Mauco et al., 1978). Platelets are a likely source of the LPA (bioassay) observed in the cerebrospinal fluid following hemorrhagic injury; in contrast, no LPA is detectible in the cerebrospinal fluid prior to injury (Tigyi et al., 1995). This finding is but one indication that LPA is likely to be a significant biomediator in the brain. The brain is a rich source of both LPA and LPA receptors, and enzymes for the biosynthesis and degradation of LPA have been isolated from the brain (Das and Hajra, 1989; van der Bend et al., 1992; Thomson et al., 1994; Thompson and Clark, 1994; Thomson and Clark, 1995). Moreover, brain tumor-derived cells, glioma and neuroblastoma cells, are responsive to LPA (Smalheiser and Ali, 1994; Koschel and Tas, 1993). Thus, studies were initiated in this laboratory to define the functions of LPA in normal cells of the brain. This study focuses on the LPA-induced responses of astrocytes derived from neonatal rat brains.