The fast and slow ups and downs of HCN channel regulation

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.