Monovalent cations contribute to T-type calcium channel (Ca_v3.1 and Ca_v3.2) selectivity

Low voltage-activated (LVA) Ca²⁺ channels regulate chemical signaling by their ability to select for Ca²⁺. Whereas Ca ²⁺ is the main permeating species through Ca²⁺ channels, Ca²⁺ permeation may be modified by abundant intra- and extracellular monovalent cations. Therefore, we explored monovalent cation regulation of LVA Ca²⁺ permeation in the cloned T-type Ca²⁺ channels α1G (Ca_v3.1) and α1H (Ca_v3.2). In physiological [Ca²⁺], the reversal potential in symmetrical Li ⁺ was 19 mV in α1G and 18 mV in α1H, in symmetrical Cs⁺ the reversal potential was 36 mV in α1G and 37 mV in α1H, and in the bi-ionic condition with Li⁺ in the bath and Cs⁺ in the pipette, the reversal potential was 46 mV in both α1G and α1H. When Cs⁺ was used in the pipette, replacement of external Cs⁺ with Li⁺ (or Na⁺) shifted the reversal potential positive by 5-6 mV and increased the net inward current in α1G. Taken together the data indicate that in physiological [Ca²⁺], external Li⁺ (or Na⁺) permeates more readily than external Cs⁺, resulting in a positive shift of the reversal potential. We conclude that external monovalent cations dictate T-type Ca²⁺ channel selectivity by permeating through the channel. Similar to Li⁺, we previously reported that external [H⁺] can regulate T-type Ca²⁺ channel selectivity. α1H's selectivity was more sensitive to external pH changes compared to α1G. When Cs ⁺ was used in the pipette and Li⁺ was used in the bath external acidification from pH_o 7.4 to 6.0 caused a negative shift of the reversal by 8 mV in α1H. Replacement of internal Cs⁺ with Li⁺ reduced the pH-induced shift of the reversal potential to 2 mV. We conclude that, similar to other external monovalent cations, H ⁺ can modify T-type Ca²⁺ channel selectivity. However, in contrast to external monovalent ions that readily permeate, H⁺ regulate T-type Ca²⁺ channel selectivity by increasing the relative permeability of the internal monovalent cation.