inositol-1-4-5-trisphosphate and Hyperplasia

Platelets are increasingly recognized for their contributions to tumor metastasis. Here, we show that the phosphoinositide signaling modulated by phosphatidylinositol transfer protein type α (PITPα), a protein which shuttles phosphatidylinositol between organelles, is essential for platelet-mediated tumor metastasis. PITPα-deficient platelets have reduced intracellular pools of phosphoinositides and an 80% reduction in IP

Topics: Animals; Anticoagulants; Blood Platelets; Fibrin; Gene Deletion; Hemostasis; Hyperplasia; Immunity, Mucosal; Inositol 1,4,5-Trisphosphate; Integrases; Lung Neoplasms; Lymphoid Tissue; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Phospholipid Transfer Proteins; Platelet Aggregation; Signal Transduction; Thrombin; Thrombosis

In rat pituitary cells from estrogen-induced hyperplasia, angiotensin II (ANG II) does not evoke a clear spike elevation of intracellular Ca2+ concentration ([Ca2+]i) but induces a plateau increase. The present work was undertaken to establish whether this difference was related to a differential participation of intracellular and/or plasma membrane Ca2+ channels. We first tested the effect of 10 nM ANG II on [Ca2+]i in the absence of extracellular Ca2+ in cells depolarized with 25 mM K+ or in the presence of blockers of L-type voltage-sensitive Ca2+ channels (VSCC). These treatments did not alter spike elevation in [Ca2+]i in controls but reduced plateau levels in hyperplastic cells. Intracellular Ca2+ stores were similar in both groups, as assessed by thapsigargin treatment, but this drug abolished spike increase in controls and scarcely modified plateau levels in hyperplastic cells. Finally, inositol trisphosphate (InsP3) production in response to ANG II was significantly higher in control cells. We conclude that the observed plateau rise in hyperplastic cells results mainly from Ca2+ influx through VSCC. In contrast, in control cells, the ANG II-induced spike increase in [Ca2+]i results from mobilization of Ca2+ from thapsigargin-sensitive internal channels, activated by higher inositol 1,4,5-trisphosphate generation.

Topics: Angiotensin II; Animals; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Female; Hyperplasia; Inositol 1,4,5-Trisphosphate; Intracellular Membranes; Pituitary Gland; Potassium; Rats; Rats, Sprague-Dawley; Reference Values; Thapsigargin

The mammalian anx7 gene codes for a Ca(2+)-activated GTPase, which supports Ca(2+)/GTP-dependent secretion events and Ca(2+) channel activities in vitro and in vivo. To test whether anx7 might be involved in Ca(2+) signaling in secreting pancreatic beta cells, we knocked out the anx7 gene in the mouse and tested the insulin-secretory properties of the beta cells. The nullizygous anx7 (-/-) phenotype is lethal at embryonic day 10 because of cerebral hemorrhage. However, the heterozygous anx7 (+/-) mouse, although expressing only low levels of ANX7 protein, is viable and fertile. The anx7 (+/-) phenotype is associated with a substantial defect in insulin secretion, although the insulin content of the islets, is 8- to 10-fold higher in the mutants than in the normal littermate control. We infer from electrophysiological studies that both glucose-stimulated secretion and voltage-dependent Ca(2+) channel functions are normal. However, electrooptical recordings indicate that the (+/-) mutation has caused a change in the ability of inositol 1,4,5-trisphosphate (IP(3))-generating agonists to release intracellular calcium. The principle molecular consequence of lower anx7 expression is a profound reduction in IP(3) receptor expression and function in pancreatic islets. The profound increase in islets, beta cell number, and size may be a means of compensating for less efficient insulin secretion by individual defective pancreatic beta cells. This is a direct demonstration of a connection between glucose-activated insulin secretion and Ca(2+) signaling through IP(3)-sensitive Ca(2+) stores.

Topics: Animals; Annexin A7; Calcium; Calcium Channels; Calcium Signaling; Cell Line; Cytosol; Electrophysiology; Genetic Vectors; Glucose; GTP Phosphohydrolases; Hyperplasia; Hypertrophy; Immunohistochemistry; Inositol 1,4,5-Trisphosphate; Inositol 1,4,5-Trisphosphate Receptors; Insulin; Insulin Secretion; Islets of Langerhans; Mice; Mice, Knockout; Mutagenesis; Phenotype; Receptors, Cytoplasmic and Nuclear