A family of hyperpolarization-activated mammalian cation channels

Abstract

Pacemaker activity of spontaneously active neurons and heart cells is controlled by a depolarizing, mixed Na+/K+ current, named Ih (or I(f) in the sinoatrial node of the heart). This current is activated on hyperpolarization of the plasma membrane. In addition to depolarizing pacemaker cells, Ih is involved in determining the resting membrane potential of neurons and provides a mechanism to limit hyperpolarizing currents in these cells. Hormones and neurotransmitters that induce a rise in cyclic AMP levels increase Ih by a mechanism that is independent of protein phosphorylation, and which involves direct binding of the cyclic nucleotide to the channel that mediates Ih. Here we report the molecular cloning and functional expression of the gene encoding a hyperpolarization-activated cation channel (HAC1) that is present in brain and heart. This channel exhibits the general properties of Ih channels. We have also identified full-length sequences of two related channels, HAC2 and HAC3, that are specifically expressed in the brain, indicating the existence of a family of hyperpolarization-activated cation channels.

Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain

“…Previous studies have suggested that each HCN subunit can form homomeric channels with different functional properties; homomeric channels of HCN1 activate rapidly on hyperpolarization (in tens of milliseconds) and show a minimal response to cAMP (Santoro et al, 1998), while those of HCN2 activate more slowly (hundreds of milliseconds) and are modulated strongly by cAMP (Ludwig et al, 1998). Activation of HCN3 homomeric channels is even slower (Moosmang et al, 2001), and that of HCN4 channels is the slowest (seconds) (Ishii et al, 1999).…”

“…Four members of a gene family encoding the mammalian Hyperpolarization-activated and Cyclic-Nucleotide-gated nonselective cation channels (HCNs: HCN1-4), which generate I h , have been cloned (Ludwig et al, 1998;Santoro et al, 1998;Ishii et al, 1999;Seifert et al, 1999).…”

Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures

“…Homomeric HCN1 channels conduct fastkinetic currents with modest cAMP gating, consistent with currents recorded in hippocampal pyramidal cells and CA1 interneurons where HCN1 expression is high (Bender et al, 2001;Brewster et al, 2002;Santoro et al, 2000). By contrast, homomeric HCN2 channels conduct I h currents with slower kinetics and robust cAMP-evoked shifts in voltage dependence (Ludwig et al, 1998;Robinson and Siegelbaum, 2003). More recently, the formation of heteromeric channels in vitro (Chen et al, 2001b;Er et al, 2003;Much et al, 2003;Proenza et al, 2002;Ulens and Tytgat, 2001;Xue et al, 2002) as well as in vivo (Er et al, 2003;Much et al, 2003) has been described.…”

Control of neuronal excitability by Group I metabotropic glutamate receptors

“…Sensitivity to cAMP makes I h currents susceptible to modulation by GPCRs, perhaps most famously exemplified by the effect of adrenaline acting though Β-adrenergic receptors and cardiac HCN channels to accelerate the heart rate (Brown et al 1979). HCN isoforms are expressed in the brain (Ludwig et al 1998;Santoro et al 1998) where they modulate excitability and action potential firing patterns (reviewed by Shah 2014). In addition to modulation by cAMP, HCN channels are inhibited by PKC-dependent pathways (Brager and Johnston 2007;Cathala and Paupardin-Tritsch 1997;Williams et al 2015).…”