In Drosophila eye, photostimulation of rhodopsin leads to activation of the Ca 2ϩ -permeable transient receptor potential (TRP) 1 and trp-like (TRPL) channels (1-3). This response, which depends on phospholipase C, is extremely rapid and results in depolarization of the photoreceptor cell followed by Ca 2ϩ -mediated feedback regulation of the visual signaling cascade. The biochemical or biophysical link between stimulation of PLC and channel activation remains unknown. Originally it was proposed that TRP and TRPL were store-operated channels (SOC) (2), i.e. channels activated by depletion of Ca 2ϩ from inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 )-sensitive internal Ca 2ϩ stores. More recent studies (4, 5) suggest that hydrolysis of phosphatidylinositol 4,5,-bisphosphate and the concomitant generation of diacylglycerol play a direct role in channel activation. Heterologous expression of TRPL gives rise to Ca 2ϩ -permeable, non-selective cation channels that are unaffected by depletion of internal stores but are activated following stimulation of membrane receptors linked to phosphoinositide turnover (6 -11). In contrast, recombinant TRP is more selective for Ca 2ϩ and is activated by depletion of internal stores by thapsigargin (9, 12). These studies strongly support the hypothesis that TRP and TRPL proteins form the essential subunit structure of the channels responsible for light-induced conductance change in Drosophila photoreceptor cells.Studies in photoreceptor cells have shown that TRP channels are held in a signaling complex (i.e. a signalplex) by a scaffolding protein called . INAD contains five tandem PDZ domains that are thought to act as protein-binding modules mediating the clustering of membrane and membraneassociated proteins. INAD has been shown to interact through the PDZ domains with itself and with a number of proteins involved in the phototransduction cascade including PLC, protein kinase C, rhodopsin, TRP, and TRPL, thus potentially creating clusters of signaling complexes (17). Studies have also shown that calmodulin (CaM) associates with the signalplex possibly by direct binding to INAD and/or TRP and TRPL. In Drosophila this signalplex appears to be an essential structural
The RAF-MEK-ERK pathway regulates both myoblast proliferation and differentiation; however, it is unclear how these events are coordinated. Here, we show that human phosphatidylethanolamine-binding protein 4 (PEBP4), a RAF kinase inhibitory protein (RKIP) family protein expressed preferentially in muscle, regulates the activity of the ERK pathway and myoblast differentiation by acting as a scaffold protein. In contrast to RKIP, which disrupts the RAF1-MEK interaction, PEBP4 forms ternary complexes with RAF1 and MEK, and can scaffold this interaction. PEBP4 expression is induced during the differentiation of primary human myoblasts. Consistent with the properties of a scaffold, PEBP4 enhances the RAF1-MEK interaction and the activation of MEK at low expression levels, whereas it inhibits these parameters at higher expression levels. Downregulation of PEBP4 by short hairpin RNA in human myoblasts increases MEK signalling and inhibits differentiation; by contrast, PEBP4 overexpression enhances differentiation. Thus, PEBP4 participates in the control of muscle cell differentiation by modulating the activity of MEK and ERK.
Recent findings have suggested that the vertebrate trp family of channel proteins is the structural basis for Ca 2+ influx through the capacitative calcium entry (CCE) pathway. We have discerned, in bovine aortic endothelial cells, the concomitant expression of four such vertebrate genes: trp-1 (two splice variants), trp-3, trp-4 and trp-5. Exogenous hormones rendered dynamic effects on the transcript levels of these genes. Most notably, ß-estradiol significantly down-regulated trp-4 while frans-retinoic acid dramatically up-regulated trp-5; yet these hormones rendered little change in CCE. These findings suggest that the extent of a given trp channel's participation in CCE is not reflected in alterations of its transcript level.
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