Identification of a Gene Encoding a Hyperpolarization-Activated Pacemaker Channel of Brain

Abstract

The generation of pacemaker activity in heart and brain is mediated by hyperpolarization-activated cation channels that are directly regulated by cyclic nucleotides. We previously cloned a novel member of the voltage-gated K channel family from mouse brain (mBCNG-1) that contained a carboxy-terminal cyclic nucleotide-binding domain (Santoro et al., 1997) and hence proposed it to be a candidate gene for pacemaker channels. Heterologous expression of mBCNG-1 demonstrates that it does indeed code for a channel with properties indistinguishable from pacemaker channels in brain and similar to those in heart. Three additional mouse genes and two human genes closely related to mBCNG-1 display unique patterns of mRNA expression in different tissues, including brain and heart, demonstrating that these channels constitute a widely expressed gene family.

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

“…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).…”

“…Structurally, each HCN subunit consists of six transmembrane domains with a pore region between S5 and S6 and a cyclic nucleotide-binding domain in the cytoplasmic C-terminal region, having a structure similar to those of cyclic nucleotide-gated channels (Santoro et al, 1998;Ludwig et al, 1999;Santoro et al, 2000;Robinson and Siegelbaum, 2002). 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).…”

“…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).…”

Presence of functional hyperpolarisation-activated cyclic nucleotide-gated channels in clonal alpha cell lines and rat islet alpha cells

“…To date, four mammalian HCN isoforms (HCN1-4) have been cloned. Studies on isoform distribution showed that while HCN3 is found primarily in neurons [23,24], the other three isoforms are found in heart and brain [23,25]. The HCN transcripts are also detected in several other organs, including skeletal muscle and lung [24].…”

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).…”