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The role of a PDGF-activated nonselective cation channel in the proliferative response
J J Gargus1, A M Frace, F Jung
1Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322.
Abstract:
Murine fibroblasts have a 28 pS calcium- and voltage-insensitive NSC that becomes quiescent at G0 arrest and is rapidly and specifically activated by PDGF. Activation is produced by the discrete loss of long channel closures. The NSC can be rapidly and reversibly blocked with the NSAID flufenamic acid, through a prostaglandin-independent mechanism. The cell cycle (not viability) is blocked concomitantly with NSC block. A somatic cell mutant with altered NSC conductance has been isolated and used to clone the genomic locus of the channel. The mutant growth phenotype adds further support to the participation of NSC conductance in cell cycle control.
Insights
A novel non-selective cation (NSC) channel in murine fibroblasts is activated by PDGF and blocks cell cycle progression. This NSC channel
Area of Science:
- Cell Biology
- Ion Channel Physiology
- Molecular Genetics
Background:
- Murine fibroblasts possess a unique 28 pS non-selective cation (NSC) channel.
- This channel is insensitive to calcium and voltage, becoming quiescent during G0 arrest.
Purpose of the Study:
- To investigate the role of the NSC channel in cell cycle regulation.
- To identify the activation mechanism and blockers of the NSC channel.
Main Methods:
- Utilized PDGF stimulation to activate the NSC channel.
- Employed flufenamic acid, a non-steroidal anti-inflammatory drug (NSAID), to block NSC activity.
- Isolated a somatic cell mutant with altered NSC conductance.
- Cloned the genomic locus of the NSC channel using the mutant.
Main Results:
- NSC channel activation by PDGF involves the loss of long channel closures.
- Flufenamic acid reversibly blocks the NSC channel via a prostaglandin-independent pathway.
- Cell cycle progression, not cell viability, is inhibited when the NSC channel is blocked.
- The isolated mutant with altered NSC conductance exhibits a distinct growth phenotype.
Conclusions:
- The NSC channel plays a critical role in controlling cell cycle progression in fibroblasts.
- The genetic basis of the NSC channel has been identified, facilitating further research into its function.