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

TLDR

Pacemaker activity in heart and brain is mediated by hyperpolarization‑activated cation channels regulated by cyclic nucleotides. The study cloned a novel voltage‑gated K channel, mBCNG‑1, from mouse brain and proposed it as a candidate pacemaker channel. The authors used interactive cloning with the SH3 domain of N‑src to isolate mBCNG‑1, which contains a cyclic nucleotide‑binding domain. Heterologous expression of mBCNG‑1 produced a pacemaker‑like channel, and related mouse and human genes show tissue‑specific expression, indicating a widely expressed family. Published in the National Academy of Sciences, USA.

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 (39Santoro B Grant S.G.N Bartsch D Kandel E.R Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels.Proc. Natl. Acad. Sci. USA. 1997; 94: 14815-14820Crossref PubMed Scopus (224) Google Scholar) 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.