期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 288, 期 6, 页码 C1451-C1460出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00503.2004
关键词
voltage-gated chloride channel family; potassium-chloride cotransporters; peritumoral edema
资金
- NCI NIH HHS [P50-CA-97247, P50 CA097247-010003, P50 CA097247] Funding Source: Medline
- NINDS NIH HHS [R01 NS036692-08, R01-NS-36692, R01 NS036692-07, R01 NS036692-06, R01 NS036692] Funding Source: Medline
Primary brain tumors ( gliomas) often present with peritumoral edema. Their ability to thrive in this osmotically altered environment prompted us to examine volume regulation in human glioma cells, specifically the relative contribution of Cl- channels and transporters to this process. After a hyposmotic challenge, cultured astrocytes, D54-MG glioma cells, and glioma cells from human patient biopsies exhibited a regulatory volume decrease (RVD). Although astrocytes were not able to completely reestablish their original prechallenge volumes, glioma cells exhibited complete volume recovery, sometimes recovering to a volume smaller than their original volumes (VPost-RVD < V-baseline). In glioma cells, RVD was largely inhibited by treatment with a combination of Cl- channel inhibitors, 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB) and Cd2+ (VPost-RVD > 1.4* V-baseline). Volume regulation was also attenuated to a lesser degree by the addition of R-(+)-[(2-n-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5- yl) oxy] acetic acid ( DIOA), a known K+-Cl- cotransporter (KCC) inhibitor. To dissect the relative contribution of channels vs. transporters in RVD, we took advantage of the comparatively high temperature dependence of transport processes vs. channel-mediated diffusion. Cooling D54-MG glioma cells to 15 degrees C resulted in a loss of DIOA-sensitive volume regulation. Moreover, at 15 degrees C, the channel blockers NPPB + Cd2+ completely inhibited RVD and cells behaved like perfect osmometers. The calculated osmolyte flux during RVD under these experimental conditions suggests that the relative contribution of Cl- channels vs. transporters to this process is similar to 60 - 70% and similar to 30 - 40%, respectively. Finally, we identified several candidate proteins that may be involved in RVD, including the Cl- channels ClC-2, ClC-3, ClC-5, ClC-6, and ClC-7 and the transporters KCC1 and KCC3a.
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