Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.
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.
Chandler
Natalie J
NJ
Cardiovascular Research Group, Faculty of Medical and Human Sciences, University of Manchester, Core Technology Facility, 46 Grafton St, Manchester M139NT, United Kingdom.
Greener
Ian D
ID
Tellez
James O
JO
Inada
Shin
S
Musa
Hanny
H
Molenaar
Peter
P
Difrancesco
Dario
D
Baruscotti
Mirko
M
Longhi
Renato
R
Anderson
Robert H
RH
Billeter
Rudolf
R
Sharma
Vinod
V
Sigg
Daniel C
DC
Boyett
Mark R
MR
Dobrzynski
Halina
H
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
D007473:Ion Channels; D012333:RNA, Messenger