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J Membr Biol
2015 Dec 01;2486:1043-60. doi: 10.1007/s00232-015-9816-7.
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HCN Channel C-Terminal Region Speeds Activation Rates Independently of Autoinhibition.
Magee KE, Madden Z, Young EC.
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Hyperpolarization- and cyclic nucleotide-activated (HCN) channels contribute to rhythmic oscillations in excitable cells. They possess an intrinsic autoinhibition with a hyperpolarized V 1/2, which can be relieved by cAMP binding to the cyclic nucleotide binding (CNB) fold in the C-terminal region or by deletion of the CNB fold. We questioned whether V 1/2 shifts caused by altering the autoinhibitory CNB fold would be accompanied by parallel changes in activation rates. We used two-electrode voltage clamp on Xenopus oocytes to compare wildtype (WT) HCN2, a constitutively autoinhibited point mutant incapable of cAMP binding (HCN2 R591E), and derivatives with various C-terminal truncations. Activation V 1/2 and deactivation t 1/2 measurements confirmed that a truncated channel lacking the helix αC of the CNB fold (ΔαC) had autoinhibition comparable to HCN2 R591E; however, ΔαC activated approximately two-fold slower than HCN2 R591E over a 60-mV range of hyperpolarizations. A channel with a more drastic truncation deleting the entire CNB fold (ΔCNB) had similar V 1/2 values to HCN2 WT with endogenous cAMP bound, confirming autoinhibition relief, yet it surprisingly activated slower than the autoinhibited HCN2 R591E. Whereas CNB fold truncation slowed down voltage-dependent reaction steps, the voltage-independent closed-open equilibrium subject to autoinhibition in HCN2 was not rate-limiting. Chemically inhibiting formation of the endogenous lipid PIP2 hyperpolarized the V 1/2 of HCN2 WT but did not slow down activation to match ΔCNB rates. Our findings suggest a "quickening conformation" mechanism, requiring a full-length CNB that ensures fast rates for voltage-dependent steps during activation regardless of potentiation by cAMP or PIP2.
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