The fast and slow ups and downs of HCN channel regulation

Abstract

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (h channels) form the molecular basis for the hyperpolarization-activated current, I(h), and modulation of h channels contributes to changes in cellular properties critical for normal functions in the mammalian brain and heart. Numerous mechanisms underlie h channel modulation during both physiological and pathological conditions, leading to distinct changes in gating, kinetics, surface expression, channel conductance or subunit composition of h channels. Here we provide a focused review examining mechanisms of h channel regulation, with an emphasis on recent findings regarding interacting proteins such as TRIP8b. This review is intended to serve as a comprehensive resource for physiologists to provide potential molecular mechanisms underlying functionally important changes in I(h) in different biological models, as well as for molecular biologists to delineate the predicted h channel changes associated with complex regulatory mechanisms in both normal function and in disease states.

Figure 1

Directly interacting small molecule and protein regulatory mechanisms of of I_h function. See text for details on binding sites. (A) Schematic depicting HCN channel tetrameric structure. One HCN channel subunit is shown in detail. Dashed red lines indicate known sites of interaction of small molecules. (B) Schematic depicting HCN channel and known interaction sites of HCN channel interacting proteins. CNBD, cyclic nucleotide binding domain; SNL-C-terminal tripeptide of HCN1, HCN2 and HCN4.