Abstract
Hyperpolarization-activated HCN channels are modulated by direct binding of cyclic nucleotides. For HCN2 channels, cAMP shifts the voltage dependence for activation, with relatively little change in the maximal conductance. By contrast, in spHCN channels, cAMP relieves a rapid inactivation process and produces a large increase in maximum conductance. Our results suggest that these two effects of cAMP represent the same underlying process. We also find that spHCN inactivation occurs not by closure of a specialized inactivation gate, as for other voltage-dependent channels, but by reclosure of the same intracellular gate opened upon activation. Effectively, the activation gate exhibits a "desensitization to voltage," perhaps by slippage of the coupling between the voltage sensors and the gate. Differences in the initial coupling efficiency could allow cAMP to produce either the inactivation or the shift phenotype by strengthening effective coupling: a shift would naturally occur if coupling is already strong in the absence of cAMP.
| Original language | English |
|---|---|
| Pages (from-to) | 737-744 |
| Number of pages | 8 |
| Journal | Neuron |
| Volume | 41 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 4 Mar 2004 |
Bibliographical note
Funding Information:We are grateful to the members of the Yellen laboratory for helpful discussions and to Tatiana Abramson for her expert help with transfections. We thank Dr. U.B. Kaupp for the spHCN clone and Dr. M. Biel for the HCN2 clone. The work was supported by grants from the NIH-NHLBI (HL 70320 to G.Y.), a McKnight Investigator Award (to G.Y.), fellowships from the NIH-NHLBI (HL71365 to C.P.), and the Belgian American Educational Foundation (to C.M.).