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. 1999 Mar 30;96(7):4154-7.
doi: 10.1073/pnas.96.7.4154.

Calcium block of Na+ channels and its effect on closing rate

C M Armstrong  1 , G Cota
Affiliations

Calcium block of Na+ channels and its effect on closing rate

C M Armstrong et al. Proc Natl Acad Sci U S A. .

Abstract

Calcium ion transiently blocks Na+ channels, and it shortens the time course for closing of their activation gates. We examined the relation between block and closing kinetics by using the Na+ channels natively expressed in GH3 cells, a clonal line of rat pituitary cells. To simplify analysis, inactivation of the Na+ channels was destroyed by including papain in the internal medium. All divalent cations tested, and trivalent La3+, blocked a progressively larger fraction of the channels as their concentration increased, and they accelerated the closing of the Na+ channel activation gate. For calcium, the most extensively studied cation, there is an approximately linear relation between the fraction of the channels that are calcium-blocked and the closing rate. Extrapolation of the data to very low calcium suggests that closing rate is near zero when there is no block. Analysis shows that, almost with certainty, the channels can close when occupied by calcium. The analysis further suggests that the channels close preferentially or exclusively from the calcium-blocked state.

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Figures

Figure 1
Figure 1
Calcium blocks Na+ channels and speeds deactivation. Gates of the Na+ channels were activated by stepping to +60 mV and were deactivated by returning to −80 mV. gNa is proportional to the number of Na+ channels that have open (activated) gates and are not Ca2+-blocked. Compared with 2 mM Ca2+, 50 mM Ca2+ blocks weakly at +60 mV, strongly at −80 mV. Deactivation is clearly faster in 50 mM Ca2+. Solutions: 2Ca 85Na and 50Ca 85Na.
Figure 2
Figure 2
Ba2+ is an adequate substitute for Ca2+. The traces show activation and deactivation of gNa in calcium at two concentrations, and after complete replacement of calcium by barium. Channel block in 20 mM Ba2+ is slightly less than in 20 mM Ca2+ (as can be seen from the initial value of the conductance tails at −60 mV) and deactivation is slightly slower. Solutions: 2Ca 155Na, 20Ca 128Na, and 20Ba 128Na.
Figure 3
Figure 3
Conductance tails in four calcium concentrations. Block, judged from initial tail amplitude, increases with calcium concentration. Deactivation is progressively faster as block increases. Solutions: 2, 10, 20, and 50Ca 85Na.
Figure 4
Figure 4
Closing rate is roughly proportional to the fraction of the channels that are calcium-blocked. Using the data of Fig. 3, we estimated the fraction of blocked channels from initial tail amplitude. Closing rate was measured as 1/τ—i.e., the reciprocal of the time constants of the conductance tails at −80 mV. The broken line is the prediction of the model in Discussion.
Figure 5
Figure 5
Conductance tail in 20 mM Ca2+, fitted by several models. Curve a shows the predicted time course if Ca2+-blocked channels cannot close, and the closing rate constant (β1) is unaffected by calcium. For curve b, β1 is increased by a factor predicted from surface charge theory. Please see text. Solutions: 2 and 20Ca 85Na.
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