title: Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.
abstract: BACKGROUND
  Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity.
  
  
  RESULTS
  Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples. Messenger RNA (mRNA) for 120 ion channels (and some related proteins) was measured in the SN, a novel paranodal area, and the right atrium (RA). The results showed, for example, that in the SN compared with the RA, there was a lower expression of Na(v)1.5, K(v)4.3, K(v)1.5, ERG, K(ir)2.1, K(ir)6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca(v)1.3, Ca(v)3.1, HCN1, and HCN4 mRNAs. The expression pattern of many ion channels in the paranodal area was intermediate between that of the SN and RA; however, compared with the SN and RA, the paranodal area showed greater expression of K(v)4.2, K(ir)6.1, TASK1, SK2, and MiRP2. Expression of ion channel proteins was in agreement with expression of the corresponding mRNAs. The levels of mRNA in the SN, as a percentage of those in the RA, were used to estimate conductances of key ionic currents as a percentage of those in a mathematical model of human atrial action potential. The resulting SN model successfully produced pacemaking.
  
  
  CONCLUSIONS
  Ion channels show a complex and heterogeneous pattern of expression in the SN, paranodal area, and RA in humans, and the expression pattern is appropriate to explain pacemaking.
authors.affiliation: Cardiovascular Research Group, Faculty of Medical and Human Sciences, University of Manchester, Core Technology Facility, 46 Grafton St, Manchester M139NT, United Kingdom.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Chandler
authors.forename: Ian D
authors.initials: ID
authors.lastname: Greener
authors.forename: James O
authors.initials: JO
authors.lastname: Tellez
authors.forename: Shin
authors.initials: S
authors.lastname: Inada
authors.forename: Hanny
authors.initials: H
authors.lastname: Musa
authors.forename: Peter
authors.initials: P
authors.lastname: Molenaar
authors.forename: Dario
authors.initials: D
authors.lastname: Difrancesco
authors.forename: Mirko
authors.initials: M
authors.lastname: Baruscotti
authors.forename: Renato
authors.initials: R
authors.lastname: Longhi
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.forename: Rudolf
authors.initials: R
authors.lastname: Billeter
authors.forename: Vinod
authors.initials: V
authors.lastname: Sharma
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Sigg
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boyett
authors.forename: Halina
authors.initials: H
authors.lastname: Dobrzynski
mesh_terms: D054849:Cardiac Electrophysiology; D006325:Heart Atria / Q000737:chemistry*; D006329:Heart Conduction System / Q000502:physiology; D006801:Humans; D007473:Ion Channels / Q000032:analysis* / Q000235:genetics / Q000502:physiology; D008955:Models, Cardiovascular; D009206:Myocardium / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis; D012849:Sinoatrial Node / Q000737:chemistry* / Q000502:physiology; D014018:Tissue Distribution
chemical_list: D007473:Ion Channels; D012333:RNA, Messenger