Phosphatidlyinositol-3-kinase C2 beta (PI3KC2β) is a potential new target to treat IgE mediated disease.

Cross linking of the IgE receptor (FcεRI) on mast cells plays a critical role in IgE-dependent allergy including allergic rhinitis, asthma, anaphylaxis, and delayed type hypersensitivity reactions. The Ca2+ activated K+ channel, KCa3.1, plays a critical role in IgE-stimulated Ca2+ entry and degranulation in mast cells by helping to maintain a negative membrane potential, which provides an electrochemical gradient to drive Ca2+ influx. Of the 3 classes of PI3K, the class II PI3Ks are the least studied and little is known about the roles for class II PI3Ks in vivo in the context of the whole organism under normal and pathological conditions. Studying bone marrow derived mast cells (BMMC) isolated from PI3KC2β-/- mice, we now show that the class II PI3KC2β is critical for FcεRI stimulated KCa3.1 channel activation and the subsequent activation of mast cells. We found FcεRI-stimulated Ca2+ entry, cytokine production, and degranulation are decreased in BMMC isolated from PI3KC2β-/- mice. In addition, PI3KC2β-/- mice are markedly resistant to both passive cutaneous and passive systemic anaphylaxis. These findings identify PI3KC2β as a new pharmacologic target to treat IgE-mediated disease

Ion channels in innate and adaptive immunity.

Ion channels and transporters mediate the transport of charged ions across hydrophobic lipid membranes. In immune cells, divalent cations such as calcium, magnesium, and zinc have important roles as second messengers to regulate intracellular signaling pathways. By contrast, monovalent cations such as sodium and potassium mainly regulate the membrane potential, which indirectly controls the influx of calcium and immune cell signaling. Studies investigating human patients with mutations in ion channels and transporters, analysis of gene-targeted mice, or pharmacological experiments with ion channel inhibitors have revealed important roles of ionic signals in lymphocyte development and in innate and adaptive immune responses. We here review the mechanisms underlying the function of ion channels and transporters in lymphocytes and innate immune cells and discuss their roles in lymphocyte development, adaptive and innate immune responses, and autoimmunity, as well as recent efforts to develop pharmacological inhibitors of ion channels for immunomodulatory therapy

Disease-related Myotubularins Function in Endocytic Traffic in Caenorhabditis elegans

MTM1, MTMR2, and SBF2 belong to a family of proteins called the myotubularins. X-linked myotubular myopathy, a severe congenital disorder characterized by hypotonia and generalized muscle weakness in newborn males, is caused by mutations in MTM1 (Laporte et al., 1996). Charcot-Marie-Tooth types 4B1 and 4B2 are severe demyelinating neuropathies caused by mutations in MTMR2 (Bolino et al., 2000) and SBF2/MTMR13 (Senderek et al., 2003), respectively. Although several myotubularins are known to regulate phosphoinositide-phosphate levels in cells, little is known about the actual cellular process that is defective in patients with these diseases. Mutations in worm MTM-6 and MTM-9, myotubularins belonging to two subgroups, disorganize phosphoinositide 3-phosphate localization and block endocytosis in the coelomocytes of Caenorhabditis elegans. We demonstrate that MTM-6 and MTM-9 function as part of a complex to regulate an endocytic pathway that involves the Arf6 GTPase, and we define protein domains required for MTM-6 activity

Passive and systemic anaphylaxis in <i>PI3KC2β</i>^<i>-/-</i> mice.

<p>A. Mean decrease in body temperature (⁰C) of <i>PI3KC2β</i>^<i>+/+</i> and <i>PI3KC2β</i>^<i>-/-</i> mice following induction of anaphylaxis (n = 5 mice in each group). B. Mean serum histamine levels 30 minutes after induction of anaphylaxis (n = 5 mice in each group). *p<0.05 as compared to the <i>PI3KC2β</i>^<i>+/+</i>. C. Passive cutaneous anaphylaxis in <i>PI3KC2β</i>^<i>+/+</i> and <i>PI3KC2β</i>^<i>-/-</i> mice. Data are expressed as A₆₂₀ per gram of skin (n = 5 mice in each group). ∗p<0.05 compared to results for <i>PI3KC2β</i>^<i>+/+</i> mice.</p