Internal K ions modulate the action of external cations on hyperpolarization-activated inward current in rabbit...

We have investigated the effect of change in external Na+ concentration on the hyperpolarization-activated inward current (I(f)) in the presence of different internal cations. Rabbit single isolated sinoatrial node cells were studied using the whole-cell patch-clamp technique. With 140 mM K+ pipettes, lowering [Na+]o causes the fully activated I/V curve for I(f) to shift in a negative direction without a significant decrease of the slope conductance. The PNa/PK ratio, as defined by the Goldman-Hodgkin-Katz equation, is concentration-dependent: the lower the [Na+]o, the higher PNa/PK. The conductance/concentration relationship for I(f) shows saturation at low [Na+]o or [K+]o, indicating that the channel has a strong affinity for external cations. With 140 mM Cs+ pipettes, the I/V curve shows strong inward rectification and inward I(f) current decreases almost proportionally to the decrease in [Na+]o; the conductance/concentration relationship for I(f) shifts to the right suggesting that the binding affinity of the external binding site is reduced. These results suggest that the I(f) channel is a multi-ion channel with a high-affinity external binding site, the affinity of which is modulated by internal cations.