Relation between bicarbonate concentration and voltage dependence of sodium currents in freshly isolated CA1 neurons...

It recently has been shown that whole cell calcium and sodium currents are modulated by CO(2)/HCO(3)(-)-buffered saline. While the bicarbonate ion, but not CO(2), has been proven to modulate calcium currents, this information is lacking for sodium currents. Furthermore, it is not known whether the strength of modulation dependents on the bicarbonate concentration or whether it is an all-or-nothing phenomenon. To answer these questions, we used the whole cell voltage-clamp technique on freshly isolated hippocampal CA1 neurons from the rat. A voltage step from -130 to -20 mV elicited a sodium current with an amplitude of -5.1 +/- 0.5 nA (mean +/- SE, n = 17) when cells were superfused with HEPES-buffered saline. The amplitude of this current increased during a subsequent superfusion with solutions containing increasing amounts of bicarbonate and CO(2) (%CO(2)/mM HCO(3)(-): 2.5/5.6; 5.0/18; 10/37), with a maximal increment in 10% CO(2)/37 mM HCO(3)(-) of -6.9 +/- 0.8 nA. The increase in amplitude was associated with a linear negative shift (slope: -0.7 mV/mM HCO(3)(-)) of the potential of half-maximal activation (DeltaV(h,a): -19.4 +/- 1.8 mV in 10% CO(2)) but not with an alteration in the maximal conductance (g(max): HEPES: 203.1 +/- 21.0 nS and 10% CO(2)/37 mM HCO(3)(-): 207.3 +/- 21.3 nS). In addition, the potential of half-maximal inactivation (V(h,i)) shifted to more negative potentials (slope: -0.6 mV/mM HCO(3)(-)) with increasing amounts of bicarbonate and CO(2) (HEPES: -53.6 +/- 11.8 mV; 10% CO(2)/37 mM HCO(3)(-): -69.8 +/- 2.1 mV), making the amplitude of the current highly sensitive for small potential changes at resting membrane potential. The same negative shift in voltage dependence arose when cells were exposed to solutions with different amounts of bicarbonate (5.6; 18; 26 mM) but constant CO(2) (5%) with slope rates of -0.5 mV/mM HCO(3)(-) for V(h,a) and -0.5 mV/mM HCO(3)(-) for V(h,i). Again, there was no correlation between bicarbonate concentration and the size of g(max). When currents were evoked in solutions containing a constant concentration (18 mM) of bicarbonate but different amounts of CO(2) (2.5; 5.0 10%), no significant changes have been observed. The present data demonstrate that bicarbonate ions, and not CO(2), modulate voltage-gated sodium currents in a concentration-dependent manner. Because the amplitude of the sodium current becomes highly sensitive to membrane potential changes concomitant with increased bicarbonate amounts, this may be critical for the excitability of the neuronal network in situations (like metabolic acidosis, respiratoric alkalosis and hypercapnia) in which the concentration of this ion can alter.