Pacemaker channels.

The pacemaker "funny" current (I(f)) has been the object of detailed investigations since its original description in sinoatrial node myocytes in the late 1970s; its role in underlying generation of spontaneous activity and autonomic modulation of cardiac rate has been amply demonstrated. In the late 1990s four isoforms of the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels, the molecular components of native pacemaker channels, were cloned, and structure-function relation studies provided a molecular interpretation of several features of the native channels. Its role in pacemaking makes I(f) a natural target of heart rate modulating agents; several heart rate reducing molecules are known today that exert their action by specific inhibition of f-channels. Experiments aimed at determining the role of I(f) relative to other proposed pacemaker mechanisms such as SR Ca(2+) transients confirm that the I(f)-mediated rate control is a key process in pacemaker generation and autonomic control.