Abstract
Mitogen-activated protein kinase (MAPK) cascades are intriguing candidates because emerging evidence points to a crucial role for these signaling pathways in cellular proliferation and differentiation (reviewed in Seger and Krebs; Neary) as well as in tissue injury and recovery (e.g., Hu and Wieloch). These cascades consist of at least three cytoplasmic protein kinases that are activated sequentially: MAPK kinase kinase→MAPK kinase→MAPK. At least three parallel MAPK pathways have been identified; these are frequently referred to as extracellular signal regulated protein kinase (ERK), stress-activated protein kinase (SAPK)—also known as JNK for c-Jun N-terminal kinase—and p38/MAPK. The latter two cascades have been implicated in growth arrest and apoptosis (Kyriakis and Avruch). MAPK cascades are stimulated by growth or stress signals, and the activated MAPKs can target proteins in the cytoplasm, membrane, or cytoskeleton, or they can translocate to the nucleus where they activate or induce transcription factors, thereby leading to the expression of genes important in cell growth or death. Our findings indicate that MAPK cascades mediate mitogenic signaling by purinergic receptors in both rat and human astrocytes. In rat astrocytes, P2 receptors are linked to the ERK cascade and mitogenesis, whereas in human astrocytes, both P1 and P2 receptors are coupled to ERK. The signaling pathway from rat and human purinergic receptors to the ERK cascade involves protein kinase C (PKC). Studies with rat astrocytes reveal that P2Y receptors are coupled to ERK by a pathway that is independent of the PI-PLC/inositol phosphate/calcium pathway.