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Divalent cation permeability and blockade of Ca²⁺-permeant non-selective cation channels in rat adrenal zona glomerulosa cells

David P. Lotshaw and Katherine A. Sheehan

The effects of the divalent cations Ca²⁺, Mg²⁺ and Ni²⁺ on unitary Na⁺ currents through receptor-regulated non-selective cation channels were studied in inside-out and cell-attached patches from rat adrenal zona glomerulosa cells.

External Ca²⁺ caused a concentration-dependent and voltage-independent inhibition of inward Na⁺ current, exhibiting an IC₅₀ of 1·4 mM. The channel was also Ca²⁺ permeant and external Ca²⁺ shifted the reversal potential as expected for a channel exhibiting a constant Ca²⁺ : Na⁺ permeability ratio near to 4.

External and internal 2 mM Mg²⁺ caused voltage-dependent inhibition of inward and outward Na⁺ current, respectively. Modelling Mg²⁺ as an impermeant fast open channel blocker indicated that external Mg²⁺ blocked the pore at a single site exhibiting a zero voltage K_d of 5·1 mM for Mg²⁺ and located 19 % of the distance through the transmembrane electric field from the external surface. Internal Mg²⁺ blocked the pore at a second site exhibiting a K_d of 1·7 mM for Mg²⁺ and located 36 % of the distance through the transmembrane electric field from the cytosolic surface.

External Ni²⁺ caused a voltage- and concentration-dependent slow blockade of inward Na⁺ current. Modelling Ni²⁺ as an impermeant slow open channel blocker indicated that Ni²⁺ blocked the pore at a single site exhibiting a K_d of 1·09 mM for Ni²⁺ and located 13·7 % of the distance through the transmembrane electric field from the external surface.

External 2 mM Mg²⁺ increased the K_d for external Ni²⁺ binding to 1·27 mM, consistent with competition for a single binding site. Changing ionic strength did not substantially affect Ni²⁺ blockade indicating the absence of surface potential under physiological ionic conditions.

It is concluded that at least two divalent cation binding sites, separated by a high free energy barrier (the selectivity filter), are located in the pore and contribute to Ca²⁺ selectivity and permeability of the channel.

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