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Ann N Y Acad Sci. 2004 May;1015:111-21.

Pacemaker channels.

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Department of Biomolecular Sciences and Biotechnology, Laboratory of Molecular Physiology and Neurobiology, University of Milan, Italy.


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.

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