Orai Ca 2+ selective channels and cancer
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HOMEOSTATIC IMMUNE FUNCTION: MACROPHAGES REGULATE INTERSTITIAL ELECTROLYTE STORAGE AND BLOOD PRESSURE
Division for Clinical Pharmacology, Vanderbilt University, Nashville, USA
Junior Research Group 2, Interdisciplinary Center for Clinical Research, University of Erlangen,
Renal control of blood composition by urinary electrolyte and water excretion is considered sufficient for maintaining the internal environment of the interstitial space. We have found that the interstitium of the skin comprises a separate, locally-regulated compartment, where cells of the mononuclear phagocyte system (MPS) sense local interstitial hypertonicity and actively modulate the internal environment by expressing vascular endothe-lial growth factor C (VEGF-C) in response to local osmotic stress. Interfering with this MPS/VEGF-C-driven ho-meostatic response by genetic deletion of TonEBP in MPS cells prevents VEGF-C driven lymph capillary hyperplas-ia in skin, resulting in skin Cl- accumulation and saltsensitive hypertension. Whether MPS cells exert their blood pressure regulatory activity via VEGF-C/VEGFR-2-mediated increases in eNOS expression, or whether VEGF-C/VEGFR-3-driven hyperplasia of the skin lymph
capillary network is mechanistically involved, remained unclear. Selective blockade of MPS-driven VEGF-C/VEGFR-3-mediated lymph capillary hyperplasia in the skin resulted in salt-sensitive hypertension, despite increased eNOS expression via the intact VEGF-C/VEGFR-2 regulatory pathway. This salt-sensitive hypertension in response to experimental blockade of physiologic lymph capillary hyperplasia again was paralleled by increased Cl-retention in the skin. We conclude that MPS cells deploy homeostatic and blood pressure regulatory activity in response to local hypertonic electrolyte accumulation in the skin. The cutaneous immune cells apparently organize local interstitial Cl- clearance from the skin via VEGF-C/VEGFR-3-driven hyperplasia of cutaneous lymph vessels. It is unclear whether or how skin electrolyte accumulation is functionally coupled with blood pressure increase.
ORAI CA2+ SELECTIVE CHANNELS AND CANCER Trebak, M.
The State University of New York (SUNY) College of Nanoscale Science and Engineering (CNSE), Albany NY, USA
The Ca2+ sensor stromal interacting molecule 1 (STIM1) and the Ca2+ channel ORAI1 mediate the ubiquitous store-operated Ca2+ entry (SOCE) pathway activated by depletion of internal Ca2+ stores and mediated through the highly Ca2±selective, Ca2+ release-activated Ca2+ (CRAC) current. Furthermore, STIM1 and ORAI1, along with ORAI3, encode store-independent Ca2+ currents regulated by either arachidonate or its metabolite, leukotriene C4. ORAI channels are emerging as important
contributors to numerous cell functions, including proliferation, migration, differentiation, and apoptosis. Recent studies suggest critical involvement of STIM. ORAI proteins are controlling the development of several cancers including malignancies of the breast, brain, prosexpressiontate, and cervix. Here, we will present data from our group regarding the involvement of different isoforms of ORAI in native Ca2+ entry pathways in cancer cells and their contribution to malignancy.
Бюллетень сибирской медицины, 2013, том 12, № 4, с. 24−68