AJP - Cell Physiology, Vol 262, Issue 6 C1464-C1470, Copyright © 1992 by American Physiological Society
Blockers of platelet-derived growth factor-activated nonselective cation channel inhibit cell proliferation
F. Jung, S. Selvaraj and J. J. Gargus
Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322.
In serum-deprived G(o)-arrested cells, the addition of serum or growth
factors initiates a cascade of events that culminates in DNA synthesis and
mitosis. Recently, we showed that in mouse L-M(TK-) fibroblasts a 28-pS
nonselective cation channel (NS channel) becomes quiescent at G(o) arrest
and rapidly active within seconds of platelet-derived growth factor (PDGF)
or serum addition, placing this response very early in the postreceptor
signaling cascade. However, lack of specific channel blockers hindered
determination of whether channel activation was necessary for mitogenesis.
Derivatives of N-phenylanthranilic acid (DCA) have been reported to block a
pancreatic nonselective channel. Therefore, using single-channel analysis,
we examined the effect of these agents on the L-M(TK-) NS channel.
Flufenamic acid and mefenamic acid rapidly produced reversible channel
block with an inhibitory constant (Ki) approximately 10 microM.
Furthermore, the component of the macroscopic K+ efflux shown to be
mediated by the NS channel was blocked with a similar Ki value. DCA effects
on cell proliferation were tested by measuring cloning efficiency and
growth rate. Both were inhibited over the range of concentration that
affected channel activity, and a 50% inhibitory dose of 50-100 microM was
determined. This observation further substantiates the hypothesis that NS
channel activation forms a necessary component in the transduction of the
mitogenic signal from the PDGF receptor.
