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Hysteresis in human HCN4 channels: A crucial feature potentially affecting sinoatrial node pacemaking

Yong-Fu Xiao^*, Natalie Chandler, Halina Dobrzynski, Eric S. Richardson, Erica M. TenBroek, Joshua J. Wilhelm, Vinod Sharma, Anthony Varghese, Mark R. Boyett, Paul A. Iaizzo, Daniel C. Sigg

Cardiac Rhythm Disease Management, Medtronic Inc., Mounds View, MN 55112, USA； 2School of Medicine, University of Manchester, Manchester M13 9NT, UK； 3Department of Surgery and 4Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA； 5Corporate Science and Technology, Medtronic Inc., Minneapolis, MN 55432, USA； 6Computer Science Department, University of Wisconsin-River Falls, WI 54022, USA

Abstract

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. Ithas been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis.We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whetherhHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-timeRT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4current (Ih) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and actionpotential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced Ih and shifted activation in the depolarizing direction, thusmodifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed thatHCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder.Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that Ih exhibits voltage-dependent hysteresisbehavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.

Key words: HCN4 channel; hysteresis; sinoatrial node; cAMP

Received: 2009-11-14　　Accepted: 2010-01-19

Corresponding author: 萧永福　　E-mail: yong-fu.xiao@medtronic.com

Citing This Article：

Yong-Fu Xiao, Natalie Chandler, Halina Dobrzynski, Eric S. Richardson, Erica M. TenBroek, Joshua J. Wilhelm, Vinod Sharma, Anthony Varghese, Mark R. Boyett, Paul A. Iaizzo, Daniel C. Sigg. Hysteresis in human HCN4 channels: A crucial feature potentially affecting sinoatrial node pacemaking. Acta Physiol Sin 2010; 62 (1): 1-13 (in Chinese with English abstract).