Biomedical Engineering Reference
In-Depth Information
Pharmacology of Hyperpolarization-Activated
Cyclic Nucleotide-Gated (HCN) Channels
Patrick Bois, Aurelien Chatelier, Jocelyn Bescond, and Jean-Fran¸ois Faivre
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2 Molecular Structure . ......................................................................... 35
3 Basic Biophysical Properties of HCN Channel Subtypes .................................. 37
4 Role ........................................................................................... 38
5 Regulation . . .................................................................................. 39
6 Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
6.1 Alinidine (ST567) and Clonidine . . ................................................... 40
6.2 Zatebradine (UL-FS 49) and Cilobradine (DK-AH 269) ............................. 42
6.3 Ivabradine (S 16257) .................................................................. 43
6.4 ZD 7288 . . . ............................................................................. 45
7 Conclusions and Future Directions .......................................................... 46
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
Abstract The current produced by hyperpolarization-activated cyclic nucleotide-
gated (HCN) channels (termed
I
f
, cardiac pacemaker “funny” current, and
I
h
in
neurons) is also considered a “pacemaker current” because it plays a key role in
controlling the rhythmic activity of cardiac pacemaker cells and spontaneously
firing neurons. The pacemaker current is an inward current activated by voltage
hyperpolarization and modulated by intracellular cAMP. Voltage-dependent open-
ing of these pacemaker channels is directly regulated by the binding of cAMP. The
f-channels are encoded by four genes (HCN1-4) and are widely expressed through-
out the heart and central nervous system. This article summarizes the structure,
function, and regulation of these channels. Because of their relevance to cardiac
pacemaker activity, f-channels are a natural target of drugs aimed at the pharmaco-
logical control of heart rate. In this regard, several agents developed for their
