Published Online
on March 16, 2009

A more recent version of this article appeared on March 31, 2009

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Submitted on July 2, 2008
Accepted on January 23, 2009

Molecular Architecture of the Human Sinus Node. Insights Into the Function of the Cardiac Pacemaker

Natalie J. Chandler PhD, Ian D. Greener PhD, James O. Tellez PhD, Shin Inada PhD, Hanny Musa PhD, Peter Molenaar PhD, Dario DiFrancesco MD, Mirko Baruscotti PhD, Renato Longhi PhD, Robert H. Anderson MD, Rudolf Billeter PhD, Vinod Sharma PhD, Daniel C. Sigg PhD, Mark R. Boyett PhD, and Halina Dobrzynski PhD^*

From the University of Manchester (N.J.C., I.D.G., J.O.T., S.I., H.M., R.H.A., M.R.B., H.D.), Manchester, United Kingdom; Queensland University of Technology and University of Queensland (P.M.), Queensland, Australia; University of Milan (D.D., M.B., R.L.), Milan, Italy; University of Nottingham (R.B.), Nottingham, United Kingdom; and Medtronic Inc (V.S., D.C.S.), Minneapolis, Minn.

^* To whom correspondence should be addressed. E-mail: halina.dobrzynski{at}manchester.ac.uk.

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.

Methods and 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_v1.5, K_v4.3, K_v1.5, ERG, K_ir2.1, K_ir6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca_v1.3, Ca_v3.1, 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_v4.2, K_ir6.1, 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.

Key words: sinus node • action potentials • electrophysiology • genes • ion channels

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