%0 Journal Article
%T The Role of HCN Channels on Membrane Excitability in the Nervous System
%A Daisuke Kase
%A Keiji Imoto
%J Journal of Signal Transduction
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/619747
%X Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels were first reported in heart cells and are recently known to be involved in a variety of neural functions in healthy and diseased brains. HCN channels generate inward currents when the membrane potential is hyperpolarized. Voltage dependence of HCN channels is regulated by intracellular signaling cascades, which contain cyclic AMP, PIP2, and TRIP8b. In addition, voltage-gated potassium channels have a strong influence on HCN channel activity. Because of these funny features, HCN channel currents, previously called funny currents, can have a wide range of functions that are determined by a delicate balance of modulatory factors. These multifaceted features also make it difficult to predict and elucidate the functional role of HCN channels in actual neurons. In this paper, we focus on the impacts of HCN channels on neural activity. The functions of HCN channels reported previously will be summarized, and their mechanisms will be explained by using numerical simulation of simplified model neurons. 1. Introduction Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels, first identified in 1976 in the heart by Noma and Irisawa [1] and characterized by Brown and Difrancesco [2] and Weiss and his colleague [3], are cation channels that open when the membrane potential is hyperpolarized. The general structure of HCN channels resembles that of the voltage-gated K+ channels. HCN channels consist of four subunits that have six transmembrane segments [4], the canonical GYG sequence in the pore forming region, and the positively charged S4 segment [4, 5]. But the K+ permeability of HCN channels is not so selective as typical K+ channels and is permeable to Na+ [6]. Thus a typical current reversal potential of HCN channels is around £¿30£¿mV. For voltage-dependent gating, inward movement of S4 segment in response to hyperpolarization is reported [7¨C9], but molecular aspects of channel opening are still unknown. For example, HCN channels require extracellular Cl£¿ and extracellular K+ to open [4]. Cyclic-AMP-(cAMP-) binding site locates near the C terminus, and cAMP affects the voltage dependence of activation in some HCN channel isoforms [10]. Phosphatidylinositol 4,5-bisphosphate (PIP2) is also known as a modulator of HCN channels; it shifts the voltage dependence through a different mechanism from that of cAMP [11, 12]. These multifaceted features endow HCN channels to work in many functions described below. In this paper, we try to understand the physiological significance of these
%U http://www.hindawi.com/journals/jst/2012/619747/