Loss of plasma membrane cajt atpase isoform i leads to an increase in steroid/nuclear receptor activity and a concomitant loss of a1 integriN
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We have previously shown that blockade of all plasma membrane Ca 2+ AT Puse 1 {PMCAl) i.soforms leads to loss of neunte extension (Brandt, el al. l996). Because (al integrin is required for neunte extension its expression wa examined. t>l Integrin was not produced in colls expressing PMCAl antisense RNA (PMC'A1-AS). Clncocorficoids have been shown to down regulate rv l integrin expression and examination of glucocorticoid receptor ((H) activity showed it to be elevated 20-fold in PMCA1-AS. One mechanism by which los-, ofPMCA] might affect (IR activity is through the action of calreticulin, which inhibits CiR activity by binding to the receptor in a calcium dependent manner. A PMCA activity has been reported in the nuclear membrane, so it is possible that this activity was also blocked by the PMf Al-AS RNA. which would result in lowered nuclear envelope, calcium concentrations. To test whether altered caireticulin activity was involved in regulation of steroid/nuclear hormone receptor activity two different receptors were used the vitamin D3 receptor fVDR) which is sensitive to calreticulin and the peroxisome proliferator ac t.ivator receptor (PPAR,) which is insensitive to caireticuun. C'o-t ransfection of PMCAi-AS and control cells with receptor cDNAs and response element reporter gene constructs found that both VDR and PPAR activity were elevated in PMCA1-AS cells. This suggests that a mechanism other than calreticulin might be responsible for elevated GR activity. Currently alterations in calcium dependent phosjihorylation of the steroid/nuclear receptors is being.
