Journal
JOURNAL OF NEUROSCIENCE
Volume 22, Issue 5, Pages 1840-1849Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.22-05-01840.2002
Keywords
BK channel; splicing variant; glioma; cloning; expression; calcium sensitivity; iberiotoxin
Categories
Funding
- NIDDK NIH HHS [T32 DK007545, DK07545] Funding Source: Medline
- NINDS NIH HHS [R01 NS031234, R01-NS36692, R01-NS31234, R01 NS036692] Funding Source: Medline
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK007545] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS036692, R01NS031234] Funding Source: NIH RePORTER
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Voltage-dependent large-conductance Ca2+-activated K+ channels (BK channels) are widely expressed in excitable and nonexcitable cells. BK channels exhibit diverse electrophysiological properties, which are attributable in part to alternative splicing of their alpha-subunits. BK currents have been implicated in the growth control of glial cells, and BK channels with novel biophysical properties have recently been characterized in human glioma cells. Here we report the isolation, cloning, and functional characterization of glioma BK (gBK), a novel splice isoform of hSlo, the gene that encodes the alpha-subunits of human BK channels. The primary sequence of gBK is 97% identical to its closest homolog hbr5, but it contains an additional 34-amino-acid exon at splice site 2 in the C-terminal tail of BK channels. hSlo transcripts containing this novel exon are expressed ubiquitously in various normal tissues as well as in neoplasmic samples, suggesting that the novel exon may modulate important physiological functions of BK channels. Expression of gBK in Xenopus oocytes gives rise to iberiotoxin-sensitive (IbTX) currents, with an IC50 for IbTX of 5.7 nM and a Hill coefficient of 0.76. Single gBK channels have a unitary conductance of similar to250 pS, and the currents show significantly slower activation and higher Ca2+ sensitivity than hbr5. Ca2+ sensitivity was enhanced specifically at physiologically relevant [Ca2+](i) (100-500 nM). Examination of biopsies from patients with malignant gliomas has revealed specific overexpression of BK channels in gliomas compared with nonmalignant human cortical tissues. Importantly, tumor malignancy grades have correlated positively with BK channel expression, suggesting an important role for the gBK channel in glioma biology.
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