Journal of Neuroscience, Vol 5, 1570-1576, Copyright © 1985 by Society for Neuroscience
Cyclic adenosine 3':5'-monophosphate and cytosolic calcium exert opposing effects on biosynthesis of tetrodotoxin-sensitive sodium channels in rat muscle cells
SJ Sherman, J Chrivia and WA Catterall
We have previously presented evidence that electrical activity and
increased cytosolic calcium reduce the density of sarcolemmal tetrodotoxin
(TTX)-sensitive sodium channels in cultured rat muscle cells (Sherman, S.
J., and W. A. Catterall (1984) Proc. Natl. Acad. Sci. U. S. A. 81:
262-266). We show here that growth of cells in ryanodine has a biphasic
effect on sodium channel number. At low concentrations (0.3 to 10 microM)
where this drug releases calcium from the sarcoplasmic reticulum into the
cytoplasm, sodium channel number is reduced 62%; whereas, at higher
concentrations where total cellular calcium is depleted, the density of
sodium channels is increased 40% above control. These results provide
further evidence for modulation of sodium channel number by cytosolic
calcium. Growth of muscle cells in the presence of agents that mimic cyclic
AMP (cAMP) action or increase intracellular cAMP levels including
8-bromo-cyclic AMP (8-BrcAMP), cyclic nucleotide phosphodiesterase
inhibitors, and forskolin increased sodium channel density up to 125%. This
action did not involve changes in spontaneous electrical activity.
Dibutyryl cGMP had no effect. Measurement of the turnover rate of sodium
channels after block of channel accumulation by tunicamycin (1.5
micrograms/ml) gave a half- time of 18 hr for exponential decay of
TTX-sensitive sodium channels in cultured rat muscle cells after an initial
6-hr lag period. Treatments which modulate sodium channel number through
changes in cytosolic calcium or cAMP had no effect on the rate of channel
turnover. The increase of sodium channel number after inhibiton of
electrical activity or treatment with 8-BrcAMP was half-maximal at 17 hr,
consistent with an increase in the rate of sodium channel biosynthesis
and/or incorporation into the sarcolemma without a change in channel
turnover time. We conclude that cytosolic calcium decreases and cAMP
increases sodium channel number by modulating the rate of biosynthesis
and/or processing of channel components. The biochemical mechanisms of
these regulatory effects are considered.
Previous Article | Next Article
