Regulation of sinus node pacemaking and atrioventricular node conduction by HCN channels in health and disease

Mark R Boyett, Joseph Yanni, James Tellez, Annalisa Bucchi, Pietro Mesirca, Xue Cai, Sunil Jit R J Logantha, Claire Wilson, Cali Anderson, Jonathan Ariyaratnam, Luke Stuart, Shu Nakao, Eman Abd Allah, Sandra Jones, Matthew Lancaster, Robert Stephenson, Natalie Chandler, Matthew Smith, Carol Bussey, Oliver MonfrediGwilym Morris, Rudi Billeter, Matteo E Mangoni, Henggui Zhang, George Hart, Alicia D'Souza

Research output: Contribution to journalArticlepeer-review


The funny current, If, was first recorded in the heart 40 or more years ago by Dario DiFrancesco and others. Since then, we have learnt that If plays an important role in pacemaking in the sinus node, the innate pacemaker of the heart, and more recently evidence has accumulated to show that If may play an important role in action potential conduction through the atrioventricular (AV) node. Evidence has also accumulated to show that regulation of the transcription and translation of the underlying Hcn genes plays an important role in the regulation of sinus node pacemaking and AV node conduction under normal physiological conditions - in athletes, during the circadian rhythm, in pregnancy, and during postnatal development - as well as pathological states - ageing, heart failure, pulmonary hypertension, diabetes and atrial fibrillation. There may be yet more pathological conditions involving changes in the expression of the Hcn genes. Here, we review the role of If and the underlying HCN channels in physiological and pathological changes of the sinus and AV nodes and we begin to explore the signalling pathways (microRNAs, transcription factors, GIRK4, the autonomic nervous system and inflammation) involved in this regulation. This review is dedicated to Dario DiFrancesco on his retirement.

Original languageEnglish
Pages (from-to)61-85
JournalProgress in Biophysics and Molecular Biology
Early online date28 Jun 2021
Publication statusE-pub ahead of print - 28 Jun 2021

Bibliographical note

Funding Information: Many people have been involved in the work on the sinus and AV nodes in the laboratory of M.R.B. at the Universities of Leeds and Manchester since the 1980's and, on the occasion of M.R.B.'s retirement, M.R.B. would like to thank them. A special thank you is owed to Itsuo Kodama and Haruo Honjo from the University of Nagoya who introduced M.R.B. to nodal tissue, and Halina Dobrzynski who pioneered many of the strategies and techniques used and who led many of the studies reviewed here. The work was generously supported by a series of five five-year programme grants (final programme grant, PG/15/16/31330) as well as project grants, scholarships and fellowships from the British Heart Foundation to M.R.B. This work is currently supported by a British Heart Foundation Intermediate Fellowship to A.D. (FS/19/1/34035), a British Heart Foundation Ph.D. Studentship to C.A., and a Fondation Leducq grant to M.E.M., M.R.B. and others (TNE FANTASY 19CV03).


  • Cardiac conduction system
  • Cardiac arrhythmias
  • Athletic training
  • Circadian rhythm
  • Ageing
  • Heart failure
  • Ageing,Heart failure

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics


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