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Intracellular cAMP‐modulated gate in Hyperpolarization activated cation channels

Abstract Hyperpolarization‐activated nonselective cation channels (HCNs) play a pivotal role in producing rhythmic electrical activity in the heart and the nerve cells. In our previous experiments, voltage‐dependent Cd2+ access to one of the substituted cysteines in S6, T464C, supports the existence of an intracellular voltage‐dependent activation gate. Direct binding of intracellular cAMP to HCN channels also modulates gating. Here we attempted to locate the cAMP‐modulated structure that can modify the gating of HCN channels. SpHCN channels, a sea urchin homologue of the HCN family, became inactivated rapidly and intracellular cAMP removed this inactivation, resulting in about eight‐fold increase of steady‐state current level. T464C was probed with Cd2+ applied to the intracellular side of the channel. We found that access of Cd2+ to T464C was strongly gated by cAMP as well as voltage. Release of bound Cd2+ by DMPS was also gated in a cAMP‐dependent manner. Our results suggest the existence of an intracellular cAMP‐modulated gate in the lower S6 region of spHCN channels.