HCN-encoded pacemaker channels: from physiology and biophysics to bioengineering.

The depolarizing membrane ionic current I(h) (also known as I(f), "f" for funny), encoded by the hyperpolarization-activated cyclic-nucleotide-modulated (HCN1-4) channel gene family, was first discovered in the heart over 25 years ago. Later, I(h) was also found in neurons, retina, and taste buds. HCN channels structurally resemble voltage-gated K(+) (Kv) channels but the molecular features underlying their opposite gating behaviors (activation by hyperpolarization rather than depolarization) and non-selective permeation profiles (> or =25 times less selective for K(+) than Kv channels) remain largely unknown. Although I(h) has been functionally linked to biological processes from the autonomous beating of the heart to pain transmission, the underlying mechanistic actions remain largely inferential and, indeed, somewhat controversial due to the slow kinetics and negative operating voltage range relative to those of the bioelectrical events involved (e.g., cardiac pacing). This article reviews the current state of our knowledge in the structure-function properties of HCN channels in the context of their physiological functions and potential HCN-based therapies via bioengineering.